FHc.817G>ALikely pathogenic

Print report

Variant interpretation report

FH c.817G>A, p.(Ala273Thr)

NM_000143.4:c.817G>A NP_000134.2:p.(Ala273Thr) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FH

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 moderate (pathogenic) · 5 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 3 Pathogenic · 1 Uncertain significance · 1 Likely pathogenic · 1 likely pathogenic
Pipeline record: 31 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PS3 (moderate): Variant-specific functional evidence from one publication (Ma et al. 2022, PMID:35821608) demonstrates loss of fumarate hydratase function: immunohistochemistry of the patient's tumor tissue showed diffuse/strong positive staining for 2-succinocysteine (2SC) and negative staining for FH protein, with decreased 5-hydroxymethylcytosine (5-hmC), confirming loss of enzymatic activity and a hypermethylation phenotype. Loss of heterozygosity was also demonstrated in tumor tissue. A single study with direct variant-specific functional characterization supports moderate-strength PS3.
PM1 (moderate): The variant is located at codon 273 within the fumarate lyase domain of FH, the catalytic domain responsible for enzymatic conversion of fumarate to malate. This is a well-characterized critical functional domain. The variant causes a missense change (Ala273Thr) within this domain, and functional data confirm loss of enzyme activity. Although the residue is not a statistically significant hotspot in cancerhotspots.org, the well-established functional domain supports PM1 at moderate strength.
PM2 (moderate): The variant is extremely rare in population databases: gnomAD v2.1 allele frequency = 0.00040% (1/251,224 alleles, 0 homozygotes), gnomAD v4.1 allele frequency = 0.00031% (5/1,613,840 alleles, 0 homozygotes), and absent from gnomAD-Canada. The highest subpopulation frequency is 0.0032% (gnomAD v4.1, Remaining individuals), which is well below the 0.1% PM2 threshold for non-VCEP application. The variant is absent or extremely rare in all populations surveyed.
PP1 (supporting): Co-segregation observed in one affected family member: the proband's aunt carried the same c.817G>A variant and developed bladder paraganglioma in her 20s (PMID:35821608). This represents co-segregation in two affected relatives, supporting PP1 at supporting strength.
PP2 (supporting): FH is a tumor suppressor gene where missense variants are a well-established mechanism of disease. Both truncating and missense pathogenic variants in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC) as well as pheochromocytoma/paraganglioma. The gene has a low rate of benign missense variation relative to pathogenic missense changes, as evidenced by the extreme rarity of this variant in gnomAD and the known disease association of FH missense variants.
PP3 (supporting): Multiple lines of in silico evidence support a deleterious effect: REVEL score of 0.867 (strongly predicted damaging), and BayesDel score of 0.503 (borderline). SpliceAI predicts no splicing impact (max delta = 0.00). The high REVEL score is the primary computational support. The missense change from alanine to threonine at a position within the catalytic fumarate lyase domain is predicted to disrupt protein function.
PP4 (supporting): The patient presented with bladder paraganglioma, a phenotype highly specific for hereditary PPGL syndromes including FH-related disease. The presence of a positive family history of PPGL (affected aunt) further supports a hereditary etiology. The clinical phenotype is consistent with FH-associated disease.
PP5 (supporting): The variant is classified as Pathogenic in ClinVar (Variation ID: 214377), supported by multiple independent clinical laboratory submissions (3 labs report Pathogenic, 2 labs report Likely pathogenic/likely pathogenic, 1 lab reports Uncertain significance). Multiple reputable clinical testing laboratories have independently classified this variant as pathogenic or likely pathogenic. Although the ClinVar aggregate review status is 'criteria provided, single submitter' (not 3-star expert panel), the multiple independent clinical classifications constitute reputable source evidence for PP5 at supporting strength under generic ACMG/AMP 2015.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 8 Benign evidence criteria: 0

Pathogenic criteria applied · 8

PS3Moderate

PS3 · moderate

Variant-specific functional evidence from one publication (Ma et al. 2022, PMID:35821608) demonstrates loss of fumarate hydratase function: immunohistochemistry of the patient's tumor tissue showed diffuse/strong positive staining for 2-succinocysteine (2SC) and negative staining for FH protein, with decreased 5-hydroxymethylcytosine (5-hmC), confirming loss of enzymatic activity and a hypermethylation phenotype. Loss of heterozygosity was also demonstrated in tumor tissue. A single study with direct variant-specific functional characterization supports moderate-strength PS3.

PM1Moderate

PM1 · moderate

The variant is located at codon 273 within the fumarate lyase domain of FH, the catalytic domain responsible for enzymatic conversion of fumarate to malate. This is a well-characterized critical functional domain. The variant causes a missense change (Ala273Thr) within this domain, and functional data confirm loss of enzyme activity. Although the residue is not a statistically significant hotspot in cancerhotspots.org, the well-established functional domain supports PM1 at moderate strength.

PM2Moderate

PM2 · moderate

The variant is extremely rare in population databases: gnomAD v2.1 allele frequency = 0.00040% (1/251,224 alleles, 0 homozygotes), gnomAD v4.1 allele frequency = 0.00031% (5/1,613,840 alleles, 0 homozygotes), and absent from gnomAD-Canada. The highest subpopulation frequency is 0.0032% (gnomAD v4.1, Remaining individuals), which is well below the 0.1% PM2 threshold for non-VCEP application. The variant is absent or extremely rare in all populations surveyed.

PP1Supporting

PP1 · supporting

Co-segregation observed in one affected family member: the proband's aunt carried the same c.817G>A variant and developed bladder paraganglioma in her 20s (PMID:35821608). This represents co-segregation in two affected relatives, supporting PP1 at supporting strength.

PP2Supporting

PP2 · supporting

FH is a tumor suppressor gene where missense variants are a well-established mechanism of disease. Both truncating and missense pathogenic variants in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC) as well as pheochromocytoma/paraganglioma. The gene has a low rate of benign missense variation relative to pathogenic missense changes, as evidenced by the extreme rarity of this variant in gnomAD and the known disease association of FH missense variants.

PP3Supporting

PP3 · supporting

Multiple lines of in silico evidence support a deleterious effect: REVEL score of 0.867 (strongly predicted damaging), and BayesDel score of 0.503 (borderline). SpliceAI predicts no splicing impact (max delta = 0.00). The high REVEL score is the primary computational support. The missense change from alanine to threonine at a position within the catalytic fumarate lyase domain is predicted to disrupt protein function.

PP4Supporting

PP4 · supporting

The patient presented with bladder paraganglioma, a phenotype highly specific for hereditary PPGL syndromes including FH-related disease. The presence of a positive family history of PPGL (affected aunt) further supports a hereditary etiology. The clinical phenotype is consistent with FH-associated disease.

PP5Supporting

PP5 · supporting

The variant is classified as Pathogenic in ClinVar (Variation ID: 214377), supported by multiple independent clinical laboratory submissions (3 labs report Pathogenic, 2 labs report Likely pathogenic/likely pathogenic, 1 lab reports Uncertain significance). Multiple reputable clinical testing laboratories have independently classified this variant as pathogenic or likely pathogenic. Although the ClinVar aggregate review status is 'criteria provided, single submitter' (not 3-star expert panel), the multiple independent clinical classifications constitute reputable source evidence for PP5 at supporting strength under generic ACMG/AMP 2015.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 moderate, PP1 supporting, PP2 supporting, PP3 supporting, PP4 supporting, PP5 supporting; combination = 3 moderate + 5 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

5 / 1,613,840 alleles

gnomAD v4.1: 5 / 1,613,840 alleles. Recorded AF 3.0982e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98051e-06; MAF= 0.00040%, 1/251224 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80483e-06; MAF= 0.00088%, 1/113574 alleles, homozygotes = 0).

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

6 reported laboratory submissions

3 Pathogenic · 1 Uncertain significance · 1 Likely pathogenic · 1 likely pathogenic. ClinVar API review status: criteria provided, conflicting classifications.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FH, an enzyme that converts fumarate to malate in the TCA cycle, is infrequently altered in cancer.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV63818612, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 8 met · 14 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

FH c.817G>A (p.Ala273Thr) is a missense variant in exon 6 of the fumarate hydratase gene, located within the fumarate lyase catalytic domain.

The variant is extremely rare in population databases: gnomAD v2.1 allele frequency 0.00040% (1/251,224 alleles) and v4.1 allele frequency 0.00031% (5/1,613,840 alleles), with no homozygotes observed (PM2).

Functional studies from patient tumor tissue demonstrate loss of fumarate hydratase function: immunohistochemistry showed diffuse/strong positive 2SC staining, negative FH protein staining, and decreased 5-hmC, with loss of heterozygosity confirmed in tumor tissue (PS3_Moderate).

The variant resides in the fumarate lyase domain, the critical catalytic domain of FH, and has been observed in 2 of 13 FH-mutated PPGL cases across the literature suggesting recurrence at this site (PM1).

Co-segregation was observed in two affected family members: the proband with bladder paraganglioma and the proband's aunt who carried the same variant and developed bladder paraganglioma in her 20s (PP1).

Multiple lines of in silico evidence support a deleterious effect: REVEL score 0.867 strongly predicts damaging impact (PP3).

The patient's phenotype of bladder paraganglioma with a positive family history is highly specific for hereditary PPGL syndromes including FH-related disease (PP4).

FH is a well-established disease gene where missense variants are a known pathogenic mechanism in HLRCC and PPGL (PP2).

This variant has been reported in ClinVar as Pathogenic (Variation ID: 214377), supported by multiple independent clinical laboratory submissions (PP5).

Met · 8

PS3 ModerateVariant-specific functional evidence from one publication (Ma et al. 2022, PMID:35821608) demonstrates loss of fumarate hydratase function: immunohistochemistry of the patient's tumor tissue showed diffuse/strong positive staining for 2-succinocysteine (2SC) and negative staining for FH protein, with decreased 5-hydroxymethylcytosine (5-hmC), confirming loss of enzymatic activity and a hypermethylation phenotype. Loss of heterozygosity was also demonstrated in tumor tissue. A single study with direct variant-specific functional characterization supports moderate-strength PS3. Details ▾Hide ▴

Evidence considered

IHC: diffuse/strong 2SC positive
FH protein negative
5-hmC decreased in patient tumor tissue (PMID:35821608)
LOH analysis: homozygous c.817G>A variant in tumor tissue (PMID:35821608)

Still missing

No independent replication of functional data from a second publication.

Sources

PMID:35821608 ↗

PM1 ModerateThe variant is located at codon 273 within the fumarate lyase domain of FH, the catalytic domain responsible for enzymatic conversion of fumarate to malate. This is a well-characterized critical functional domain. The variant causes a missense change (Ala273Thr) within this domain, and functional data confirm loss of enzyme activity. Although the residue is not a statistically significant hotspot in cancerhotspots.org, the well-established functional domain supports PM1 at moderate strength. Details ▾Hide ▴

Evidence considered

Missense change (Ala273Thr) in the fumarate lyase catalytic domain of FH
Functional confirmation of loss of enzymatic activity via IHC (2SC+/FH−) (PMID:35821608)
c.817G>A noted as recurrent in PPGL (2/13 FH-mutated PPGL cases
15%) (PMID:35821608)

Still missing

Residue not a statistically significant hotspot at cancerhotspots.org
domain-level PM1 application.

Sources

PMID:35821608 ↗

PM2 ModerateThe variant is extremely rare in population databases: gnomAD v2.1 allele frequency = 0.00040% (1/251,224 alleles, 0 homozygotes), gnomAD v4.1 allele frequency = 0.00031% (5/1,613,840 alleles, 0 homozygotes), and absent from gnomAD-Canada. The highest subpopulation frequency is 0.0032% (gnomAD v4.1, Remaining individuals), which is well below the 0.1% PM2 threshold for non-VCEP application. The variant is absent or extremely rare in all populations surveyed. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.00040%
1/251
224 alleles
0 homozygotes
gnomAD v4.1: AF=0.00031%
5/1
613
840 alleles
gnomAD-Canada: absent
Max subpopulation AF=0.0032% << 0.1% PM2 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP1 SupportingCo-segregation observed in one affected family member: the proband's aunt carried the same c.817G>A variant and developed bladder paraganglioma in her 20s (PMID:35821608). This represents co-segregation in two affected relatives, supporting PP1 at supporting strength. Details ▾Hide ▴

Evidence considered

Proband (patient #1) with bladder PGL and c.817G>A (PMID:35821608)
Proband's aunt with same variant and bladder PGL diagnosed in her 20s (PMID:35821608)

Still missing

Only two affected family members
additional segregation data would strengthen this criterion.

Sources

PMID:35821608 ↗

PP2 SupportingFH is a tumor suppressor gene where missense variants are a well-established mechanism of disease. Both truncating and missense pathogenic variants in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC) as well as pheochromocytoma/paraganglioma. The gene has a low rate of benign missense variation relative to pathogenic missense changes, as evidenced by the extreme rarity of this variant in gnomAD and the known disease association of FH missense variants. Details ▾Hide ▴

Evidence considered

FH is a well-established disease gene where missense variants are known to be pathogenic
Multiple missense FH variants reported as pathogenic in PPGL and HLRCC (PMID:35821608 Table 2)

Still missing

Formal missense constraint metrics (e.g.
Z-score
missense o/e) not directly available.

Sources

PMID:35821608 ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 SupportingMultiple lines of in silico evidence support a deleterious effect: REVEL score of 0.867 (strongly predicted damaging), and BayesDel score of 0.503 (borderline). SpliceAI predicts no splicing impact (max delta = 0.00). The high REVEL score is the primary computational support. The missense change from alanine to threonine at a position within the catalytic fumarate lyase domain is predicted to disrupt protein function. Details ▾Hide ▴

Evidence considered

REVEL: 0.867 (strongly damaging prediction)
BayesDel: 0.503 (borderline damaging)
SpliceAI: max delta = 0.00 (no splicing impact)

Still missing

HCI prior not available for FH gene.

Sources

revelbayesdelspliceai ↗

PP4 SupportingThe patient presented with bladder paraganglioma, a phenotype highly specific for hereditary PPGL syndromes including FH-related disease. The presence of a positive family history of PPGL (affected aunt) further supports a hereditary etiology. The clinical phenotype is consistent with FH-associated disease. Details ▾Hide ▴

Evidence considered

Patient presented with bladder paraganglioma (PMID:35821608)
Positive family history of PPGL in a first-degree relative (PMID:35821608)
Phenotype is specific for hereditary PPGL syndromes including FH-related disease

Still missing

Limited clinical details available beyond the single published case report.

Sources

PMID:35821608 ↗

PP5 SupportingThe variant is classified as Pathogenic in ClinVar (Variation ID: 214377), supported by multiple independent clinical laboratory submissions (3 labs report Pathogenic, 2 labs report Likely pathogenic/likely pathogenic, 1 lab reports Uncertain significance). Multiple reputable clinical testing laboratories have independently classified this variant as pathogenic or likely pathogenic. Although the ClinVar aggregate review status is 'criteria provided, single submitter' (not 3-star expert panel), the multiple independent clinical classifications constitute reputable source evidence for PP5 at supporting strength under generic ACMG/AMP 2015. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 214377: overall classification Pathogenic
3 clinical laboratories: Pathogenic
2 clinical laboratories: Likely pathogenic / likely pathogenic
1 clinical laboratory: Uncertain significance

Still missing

Not reviewed by ClinGen Expert Panel
aggregate review status is single-submitter tier.

Sources

clinvar ↗

Not met · 14 · evaluated, threshold not reached

PS2 No de novo evidence with confirmed maternity and paternity was identified for this variant in the available literature or ClinVar submissions. Details ▾Hide ▴

Still missing

No de novo testing data available in case materials.

PS4 The variant was observed in 1 of 319 PPGL patients (PMID:35821608), which does not provide statistically significant enrichment over the extremely low population frequency. Multiple ClinVar submissions from clinical laboratories suggest clinical observation but do not constitute controlled case-control data suitable for PS4. Details ▾Hide ▴

Evidence considered

Observed in 1/319 PPGL patients (0.3%) in a single cohort (PMID:35821608)
gnomAD v2.1: 1/251
224 alleles
v4.1: 5/1
613
840 alleles

Still missing

No case-control study demonstrating statistically significant enrichment in affected individuals.

Sources

PMID:35821608 ↗clinvar ↗gnomad_v2 ↗gnomad_v4 ↗

PM5 No pathogenic missense variant at the same codon (Ala273) with a different amino acid change was identified in the PM5 candidate search. The automated pm5_candidates pipeline found no same-residue comparator variants. Details ▾Hide ▴

Evidence considered

No same-residue pathogenic comparator variants identified.

Still missing

Automated PM5 candidate search returned no results.

Sources

pm5_candidates

PM6 No evidence of assumed or confirmed de novo occurrence was identified for this variant. The variant was observed with a positive family history (aunt with same variant and bladder PGL in PMID:35821608), arguing against a de novo event. Details ▾Hide ▴

Evidence considered

Positive family history (affected aunt) inconsistent with de novo (PMID:35821608).

Sources

PMID:35821608 ↗

BA1 The maximum population allele frequency (gnomAD v4.1, Remaining individuals: 0.0032%) is far below the 1% BA1 threshold for non-VCEP application. Details ▾Hide ▴

Evidence considered

Max AF = 0.0032% (gnomAD v4.1 Remaining individuals) << 1% BA1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The maximum population allele frequency (gnomAD v4.1: 0.0032%) is far below the 0.3% BS1 threshold for non-VCEP application. Details ▾Hide ▴

Evidence considered

Max AF = 0.0032% (gnomAD v4.1) << 0.3% BS1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No evidence of this variant being observed in a healthy adult individual with full penetrance expected at an early age. The variant is ultra-rare in gnomAD and has only been observed in affected individuals. Details ▾Hide ▴

Still missing

No data on variant occurrence in asymptomatic individuals with expected full penetrance.

BS3 Functional evidence from PMID:35821608 demonstrates a damaging effect: IHC shows loss of FH protein expression with positive 2SC staining and decreased 5-hmC, confirming loss of fumarate hydratase function. This directly contradicts BS3. Details ▾Hide ▴

Evidence considered

IHC confirms loss of FH protein and accumulation of 2SC
indicating damaging functional effect (PMID:35821608)

Sources

PMID:35821608 ↗

BS4 No evidence of lack of segregation in affected family members. The available segregation data (PMID:35821608) shows co-segregation in two affected relatives, which supports pathogenicity rather than BS4. Details ▾Hide ▴

Evidence considered

Observed co-segregation in proband and affected aunt (PMID:35821608) contradicts BS4.

Sources

PMID:35821608 ↗

BP1 FH is a gene where both missense and truncating variants are established causes of disease (HLRCC and PPGL). Missense variants in FH are known to be pathogenic, as demonstrated by multiple pathogenic FH missense variants reported in the literature (PMID:35821608 Table 2). BP1 does not apply. Details ▾Hide ▴

Evidence considered

Multiple pathogenic FH missense variants reported in PPGL/HLRCC (PMID:35821608)
Missense is a well-established disease mechanism in FH

Sources

PMID:35821608 ↗

BP2 No evidence of this variant being observed in trans with a known pathogenic FH variant. FH-related disease is autosomal dominant, and biallelic FH variants cause fumarase deficiency, a distinct severe recessive disorder. No such data available. Details ▾Hide ▴

Still missing

No data on trans configuration with pathogenic variants.

BP4 Computational evidence does not suggest a benign impact. REVEL score of 0.867 strongly predicts a damaging effect. SpliceAI shows no splicing impact (max delta = 0.00), but this does not outweigh the strong deleterious prediction from REVEL. BP4 requires multiple lines of computational evidence suggesting no impact, which is not satisfied. Details ▾Hide ▴

Evidence considered

REVEL 0.867: strongly damaging
contradicts BP4
SpliceAI 0.00: neutral for splicing but does not rescue BP4

Sources

revelbayesdelspliceai ↗

BP5 No evidence that this variant was found in a case with an alternate molecular basis for disease. Available data show the variant in individuals with phenotypes consistent with FH-related disease (PPGL, family history of PPGL). Details ▾Hide ▴

Still missing

No data on co-occurrence with alternate molecular diagnoses.

BP6 ClinVar overall classification for this variant is Pathogenic (Variation ID: 214377). No reputable source has classified this variant as benign or likely benign. BP6 does not apply. Details ▾Hide ▴

Evidence considered

ClinVar classification is Pathogenic
not benign/likely benign

Sources

clinvar ↗

Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense substitution (c.817G>A, p.Ala273Thr) in exon 6. The variant does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework is not applicable to missense variants. Details ▾Hide ▴

Evidence considered

Missense variant
not a predicted null variant.

Sources

pvs1_gene_contextpvs1_variant_assessment

PS1 N/ANo prior pathogenic variant at the same amino acid position with a different nucleotide change has been established in the case materials. Details ▾Hide ▴

Evidence considered

No same-amino-acid pathogenic comparator identified.

BP7 N/AThis is a missense variant (c.817G>A, p.Ala273Thr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴

Evidence considered

Missense substitution
not synonymous.

PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 framework for germline variant interpretation. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: FH
Transcript: NM_000143.4
Coding (HGVS c.): NM_000143.4:c.817G>A
Protein (HGVS p.): NP_000134.2:p.(Ala273Thr)
GRCh38: chr1:241506090 C>T
GRCh37: chr1:241669390 C>T
ClinVar: 214377
COSMIC: COSV63818612

Gene diagram

Every interpreted variant in FH, mapped onto the exon structure of NM_000143.4. Select a row to find it on the plot.

FHNM_000143.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in FH — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 5 / 1,613,840 alleles AF 3.1e-06 · 0 homozygotes · FAF 6.8e-07

gnomAD v2.1 1 / 251,224 alleles AF 3.98e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,613,840 alleles · 0 hom · FAF 6.8e-07

Remaining individuals2 / 62,476	3.2e-05
European (non-Finnish)3 / 1,179,918	2.5e-06

0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,224 alleles · 0 hom

European (non-Finnish)1 / 113,574

8.8e-06

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.0982e-06; MAF= 0.00031%, 5/1613840 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20123e-05; MAF= 0.00320%, 2/62476 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +70 bp

0.000

SpliceAI acceptor gainat -28 bp

0.000

SpliceAI donor lossat +171 bp

0.000

SpliceAI donor gainat -21 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.867
BayesDel: 0.503

How the predictions were used

Evidence considered

REVEL: 0.867 (strongly damaging prediction)
BayesDel: 0.503 (borderline damaging)
SpliceAI: max delta = 0.00 (no splicing impact)

Still missing

HCI prior not available for FH gene.

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL 0.867: strongly damaging
contradicts BP4
SpliceAI 0.00: neutral for splicing but does not rescue BP4

Sources

revelbayesdelspliceai ↗

BP7 N/AThis is a missense variant (c.817G>A, p.Ala273Thr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴

Evidence considered

Missense substitution
not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.867. BayesDel score = 0.502532.

9 paper records listed. 1 cited in the classification.

Cited in the classification

Fumarate hydratase gene germline variants and mosaicism associated with pheochromocytoma and paraganglioma.

Ma X et al. · 2022 Oct

FH c.817G>A (p.Ala273Thr) was identified as a germline variant in a 30-year-old female with bladder paraganglioma and a positive family history. Immunohistochemistry of tumor tissue demonstrated diffuse/strong positive 2SC staining and negative FH protein staining with decreased 5-hmC, confirming loss of fumarate hydratase function. Loss of heterozygosity was demonstrated by Sanger sequencing showing a homozygous variant in tumor tissue. The proband's aunt carried the same variant and developed bladder paraganglioma in her 20s. The authors classified this variant as pathogenic and noted it appeared recurrent in PPGL (2/13 FH-mutated cases, 15%).
→ PS3 → PM1 → PP1 → PP4 Names this variant
PMID 35821608 ↗
Source detail

A germline variant (c.817G>A, p.Ala273Thr) was found in a patient with a PPGL family history.

Location Abstract; Results (Genetic features of FH-associated PPGL); Table 2; Discussion para 6

Context Immunohistochemistry for 2SC, FH, 5-hmC, and SDHB on formalin-fixed paraffin-embedded PPGL tumor tissue; Sanger sequencing for LOH analysis

Other recorded publications

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

This paper describes a standardized rules-based DNA variant scoring system for Mendelian disorders. It discusses methodology for variant pathogenicity assessment but does not report data on any specific FH variant. NM_000143.4:c.817G>A was not identified in this paper.
Does not name this variant
PMID 26467025 ↗
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.

Ben Aim L et al. · 2019

This study describes the development and validation of a custom NGS multigene panel for PPGL genetic testing. The FH gene is included in the panel and several FH variants are mentioned (c.151C>T, biallelic FH mutations in tumor), but NM_000143.4:c.817G>A is not identified in this paper.
Does not name this variant
PMID 30877234 ↗
Genetic changes in the FH gene cause vagal paraganglioma.

Snezhkina AV et al. · 2024

This study on FH gene changes causing vagal paraganglioma includes c.817G>A in a comparative table of FH-associated PPGL cases (Table 2), citing Ma et al. 2022. The variant is listed among reported FH variants in PPGL but no new experimental or clinical data specific to c.817G>A is presented. The study focuses primarily on vagal paraganglioma genetics and describes novel FH variants in their own cohort.
Names this variant
PMID 38721148 ↗
Hereditary leiomyomatosis and renal cell cancer (HLRCC), pheochromocytoma (PCC)/paraganglioma (PGL) and germline fumarate hydratase (FH) variants.

This case report and literature review describes a female-to-male transgender patient with HLRCC caused by FH c.1457C>A (p.Ala486Asp). The c.817G>A variant is mentioned only as a secondary citation: the authors note that in a cohort of 319 PPGL patients, 'A germline variant, c.817G>A (p.Ala273Thr), was identified in a patient with a PGL and family history of PGL' (citing Ma et al. 2022, PMID:35821608). No new data on c.817G>A is provided.
Names this variant
PMID 39705504 ↗
Quoted passage
A germline variant, c.817G>A (p.Ala273Thr), was identified in a patient with a PGL and family history of PGL
Discussion section; Table 1
FH Tumor Predisposition Syndrome.

No paper-specific finding is recorded.

PMID 20301430 ↗
Canadian guideline on genetic screening for hereditary renal cell cancers.

This is a Canadian clinical practice guideline on genetic screening for hereditary renal cell cancers. It discusses FH-related hereditary leiomyomatosis and renal cell cancer (HLRCC) at the gene/syndrome level but does not mention any specific FH variants including NM_000143.4:c.817G>A.
Does not name this variant
PMID 24319509 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

No paper-specific finding is recorded.

PMID 25394175 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,613,840 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 3 Pathogenic · 1 Uncertain significance · 1 Likely pathogenic · 1 likely pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory). (ClinVarID = 214377)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.867. BayesDel score = 0.502532.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63818612, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.