0%
FHc.301C>TPathogenic
Print report
Variant interpretation report

FH c.301C>T, p.(Arg101Ter)

NM_000143.4:c.301C>T NP_000134.2:p.(Arg101Ter) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A 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.

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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong

Null variant (nonsense) in gene FH where loss of function is a known mechanism of disease for hereditary leiomyomatosis and renal cell cancer (HLRCC). The variant introduces a premature termination codon at position 101 of 511 amino acids in exon 3 of 10, predicted to trigger nonsense-mediated decay. FH is an established tumor suppressor with autosomal dominant HLRCC predisposition; truncating germline FH variants are a well-characterized cause of this syndrome. Per ClinGen SVI PVS1 recommendations (PMC6185798), a nonsense variant in a gene with established LoF disease mechanism is assigned PVS1 at full strength.

PS3Supporting
PS3 · supporting

Protein-truncating FH mutations have been demonstrated to be functionally null alleles. PMID:12761039 states that 'Protein-truncating FH mutations are functionally null alleles,' and multiple studies (PMID:16597677, PMID:21398687) have demonstrated significantly reduced FH enzymatic activity in cells from HLRCC patients harboring various FH mutations. OncoKB annotates this variant as 'Likely Loss-of-function.' While no full-text publication specifically assaying the R101* variant was identified, the functional null effect of nonsense variants in FH is well-established across the literature. The strength is downgraded to supporting because the evidence is derived from class-level functional characterization rather than a variant-specific assay.

PM2Moderate
PM2 · moderate

The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at extremely low frequency in gnomAD v4.1 (12/1,613,900 alleles, global AF = 0.00074%), all observed in the European (non-Finnish) population (12/1,179,948, subpopulation AF = 0.00102%). This frequency is well below the 0.1% threshold for PM2 in non-VCEP assessment. No homozygotes are observed.

PP5Supporting
PP5 · supporting

Multiple reputable clinical laboratories and curated databases report NM_000143.4:c.301C>T as pathogenic. ClinVar records 14 clinical laboratories classifying this variant as Pathogenic (Variation ID 16232, review status: criteria provided, single submitter). Three major clinical testing laboratories (Ambry Genetics, Invitae/Labcorp, Fulgent Genetics) and OMIM have submitted Pathogenic classifications. OncoKB annotates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect. While the evidence underlying these classifications could not be independently verified, the consensus from multiple reputable sources supports application of PP5.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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: PVS1 very strong, PS3 supporting, PM2 moderate, PP5 supporting; combination = 1 very strong + 1 moderate + 2 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

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

SpliceAI score
0.000 maximum delta

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

No listed criterion applied SpliceAI ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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.

29 criteria with recorded statuses: 4 met · 8 not met · 9 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000143.4:c.301C>T (p.Arg101Ter) is a nonsense variant in exon 3 of 10 in the FH gene, which encodes fumarate hydratase. Loss-of-function variants in FH are an established cause of autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC).

This variant introduces a premature termination codon at position 101 of 511 amino acids, predicted to trigger nonsense-mediated decay and result in complete loss of protein function. Under ClinGen SVI PVS1 guidelines, this meets criteria for PVS1 at very strong strength.

The variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at extremely low frequency in gnomAD v4.1 (12/1,613,900 alleles, AF = 0.00074%, no homozygotes), meeting PM2 at moderate strength.

Protein-truncating FH mutations have been demonstrated to be functionally null alleles in published studies, and OncoKB annotates R101* as Likely Loss-of-function, supporting a damaging functional effect at PS3 supporting strength.

This variant has been classified as Pathogenic by 14 clinical laboratories in ClinVar (Variation ID 16232) and is annotated as Likely Oncogenic by OncoKB, meeting PP5 at supporting strength.

No benign criteria are met. The variant is absent or at extremely low frequency in population databases (BA1/BS1 not met), functional evidence supports a damaging effect (BS3 not met), and no reputable source reports this variant as benign (BP6 not met).

Applying the ACMG/AMP 2015 combination rules: 1 Very Strong (PVS1) + 1 Moderate (PM2) + 2 Supporting (PS3, PP5) satisfies the threshold for Pathogenic classification.

Met · 4

PVS1 Very strongNull variant (nonsense) in gene FH where loss of function is a known mechanism of disease for hereditary leiomyomatosis and renal cell cancer (HLRCC). The variant introduces a premature termination codon at position 101 of 511 amino acids in exon 3 of 10, predicted to trigger nonsense-mediated decay. FH is an established tumor suppressor with autosomal dominant HLRCC predisposition; truncating germline FH variants are a well-characterized cause of this syndrome. Per ClinGen SVI PVS1 recommendations (PMC6185798), a nonsense variant in a gene with established LoF disease mechanism is assigned PVS1 at full strength. Details ▾Hide ▴
Evidence considered
  • Nonsense mutation c.301C>T creates premature stop codon p.Arg101Ter (R101*) in exon 3/10
  • FH loss-of-function is an established disease mechanism for HLRCC (autosomal dominant)
  • Germline pathogenic FH variants identified in 35.7% of FH-deficient uterine leiomyomas
  • truncating mutations significantly more prevalent in hereditary cases (PMID:41496563)
  • NM_000143.4 is the MANE Select transcript
  • NMD is predicted (PTC at codon 101
  • well upstream of the last exon-exon junction)
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment41496563
PS3 SupportingProtein-truncating FH mutations have been demonstrated to be functionally null alleles. PMID:12761039 states that 'Protein-truncating FH mutations are functionally null alleles,' and multiple studies (PMID:16597677, PMID:21398687) have demonstrated significantly reduced FH enzymatic activity in cells from HLRCC patients harboring various FH mutations. OncoKB annotates this variant as 'Likely Loss-of-function.' While no full-text publication specifically assaying the R101* variant was identified, the functional null effect of nonsense variants in FH is well-established across the literature. The strength is downgraded to supporting because the evidence is derived from class-level functional characterization rather than a variant-specific assay. Details ▾Hide ▴
Evidence considered
  • PMID:12761039 abstract: 'Protein-truncating FH mutations are functionally null alleles'
  • PMID:16597677: FH enzyme activity significantly reduced in HLRCC lymphoblastoid and fibroblast cell lines
  • PMID:21398687: 32 FH mutations demonstrated as deleterious by FH enzymatic activity reduction
  • OncoKB: Likely Loss-of-function
  • Likely Oncogenic for R101*
Still missing
  • No variant-specific functional assay for R101* identified
  • evidence is class-level
Sources
PMID:12761039 ↗PMID:16597677 ↗PMID:21398687 ↗oncokb ↗127610391659767721398687
PM2 ModerateThe variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at extremely low frequency in gnomAD v4.1 (12/1,613,900 alleles, global AF = 0.00074%), all observed in the European (non-Finnish) population (12/1,179,948, subpopulation AF = 0.00102%). This frequency is well below the 0.1% threshold for PM2 in non-VCEP assessment. No homozygotes are observed. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (0 alleles)
  • gnomAD v4.1: 12/1
  • 613
  • 900 alleles
  • global AF = 7.44e-06 (0.00074%)
  • 0 homozygotes
  • all in NFE subpopulation
  • gnomAD-Canada v1.0: absent
  • grpmax FAF = 5.42e-06
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP5 SupportingMultiple reputable clinical laboratories and curated databases report NM_000143.4:c.301C>T as pathogenic. ClinVar records 14 clinical laboratories classifying this variant as Pathogenic (Variation ID 16232, review status: criteria provided, single submitter). Three major clinical testing laboratories (Ambry Genetics, Invitae/Labcorp, Fulgent Genetics) and OMIM have submitted Pathogenic classifications. OncoKB annotates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect. While the evidence underlying these classifications could not be independently verified, the consensus from multiple reputable sources supports application of PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 16232: Pathogenic
  • 14 clinical laboratories
  • criteria provided (single submitter)
  • ClinVar submissions: Ambry Genetics (SCV000185776)
  • Invitae/Labcorp (SCV000632453)
  • OMIM (SCV000037892)
  • Fulgent Genetics (SCV000611195) — all Pathogenic
  • OncoKB: Likely Oncogenic
  • Likely Loss-of-function for R101*
Sources
clinvar ↗oncokb ↗

Not met · 8 · evaluated, threshold not reached

PM1 The variant is not located in a recognized mutational hotspot for FH. Cancer Hotspots does not list residue R101 as a statistically significant hotspot. Published data (PMID:41496563) identifies exons 5 and 7 in the fumarate lyase domain as the predominant FH mutational hotspots, while c.301C>T is in exon 3. Although the variant lies within the fumarate lyase domain broadly, the absence of hotspot-level mutation clustering at this residue precludes application of PM1. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no residue-level hotspot at R101
  • PMID:41496563: exons 5 and 7 are predominant FH mutational hotspots
  • not exon 3
Sources
hotspots ↗41496563
PP3 Insufficient computational evidence to support a deleterious effect. SpliceAI predicts no splice-altering impact (max delta score = 0.00). BayesDel score is borderline at 0.486, below typical deleterious thresholds. REVEL is unavailable for this variant. No multiple lines of in silico evidence converge on a deleterious prediction to satisfy PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00 (no splice impact predicted)
  • BayesDel: score 0.486 (borderline
  • not in damaging range)
  • REVEL: not available for this variant
Sources
spliceai ↗bayesdel
BA1 The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 0.00074%). BA1 requires an allele frequency >5% in population databases, which is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 global AF = 0.00074%
  • far below 5% BA1 threshold
Sources
gnomad_v4 ↗
BS1 The variant is present in gnomAD v4.1 at a global AF of 0.00074% (grpmax FAF = 5.42e-06). For non-VCEP assessment, the BS1 threshold is >0.3%. The observed frequency is far below this threshold, so BS1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 global AF = 0.00074%
  • grpmax FAF = 5.42e-06
  • both far below 0.3% BS1 threshold
Sources
gnomad_v4 ↗
BS2 The variant is observed in gnomAD v4.1 at very low frequency (12/1,613,900 alleles, all in the NFE population, 0 homozygotes). However, HLRCC is an adult-onset disorder (cutaneous/uterine leiomyomas and renal cell cancer typically manifest in adulthood), so observation in a general population database where individuals may not have reached the age of disease penetrance does not constitute convincing evidence for BS2. BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 12 alleles in NFE
  • no homozygotes
  • HLRCC is adult-onset
  • gnomAD observations do not rule out future disease manifestation
Sources
gnomad_v4 ↗
BS3 BS3 requires well-established functional studies showing no damaging effect on protein function or splicing. The available functional evidence for FH truncating variants consistently supports a damaging (loss-of-function) effect, not a benign effect. BS3 is not met. Details ▾Hide ▴
Evidence considered
  • PMID:12761039: truncating FH mutations are functionally null alleles
  • PMID:16597677
  • PMID:21398687: reduced FH enzymatic activity in HLRCC
  • Functional evidence supports damaging effect
  • not benign
Sources
PMID:12761039 ↗PMID:16597677 ↗PMID:21398687 ↗127610391659767721398687
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI predicts no splice impact (max delta = 0.00), which is one line of non-damaging evidence. However, BayesDel is borderline (0.486) and REVEL is unavailable, so there are not multiple lines of computational evidence converging on a benign prediction. A single non-damaging SpliceAI score is insufficient for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.00 (no splice impact)
  • BayesDel: 0.486 (borderline
  • not conclusive for benign)
  • REVEL: not available
  • Only one clear line of benign computational evidence — insufficient for BP4
Sources
spliceai ↗bayesdel
BP6 BP6 requires a reputable source to report the variant as benign. All available ClinVar submissions classify this variant as Pathogenic; OncoKB classifies it as Likely Oncogenic. No reputable source reports this variant as benign, so BP6 is not met. Details ▾Hide ▴
Evidence considered
  • ClinVar: 14 clinical laboratories report Pathogenic
  • 0 report Benign
  • OncoKB: Likely Oncogenic (not benign)
Sources
clinvar ↗oncokb ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo observation with confirmed paternity and maternity was identified in the available evidence. No full-text publications mentioning this specific variant were available for review. Details ▾Hide ▴
Still missing
  • No de novo data identified for NM_000143.4:c.301C>T
PS4 No formal case-control study or statistically significant enrichment data specific to NM_000143.4:c.301C>T was identified in the available evidence. ClinVar reports this variant as Pathogenic by 14 clinical laboratories, suggesting multiple independent observations, but without formal case-control statistics this does not satisfy PS4. Details ▾Hide ▴
Evidence considered
  • ClinVar: classified as Pathogenic by 14 clinical laboratories (suggestive of multiple observations but insufficient for formal PS4)
Still missing
  • Case-control data or variant-specific enrichment analysis not available
PM6 No de novo observation (without confirmed paternity and maternity) was identified for this variant in the available evidence. PM6 requires a de novo observation without parental confirmation; no such data was found. Details ▾Hide ▴
Still missing
  • No de novo data identified for NM_000143.4:c.301C>T
PP1 No co-segregation data for NM_000143.4:c.301C>T with disease in multiple affected family members was identified in the available evidence. Details ▾Hide ▴
Still missing
  • No segregation data available for this variant
PP4 No patient-specific phenotype or family history data were available for review. PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology; this cannot be evaluated without clinical context. Details ▾Hide ▴
Still missing
  • No patient phenotype data available
BS4 No segregation data were available to assess lack of co-segregation with disease in affected family members. BS4 cannot be evaluated without family-level segregation analysis. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No data were available regarding observation of this variant in trans with a known pathogenic FH variant. BP2 applies to variants observed in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
  • No trans configuration data available
BP5 No data were available regarding observation of this variant in a case with an alternate molecular basis for disease. BP5 cannot be evaluated without case-level molecular data. Details ▾Hide ▴
Still missing
  • No case-level molecular data with alternate disease basis available
PS5 PS5 requires an established pathogenic variant at the same nucleotide position (typically a different nucleotide change at the same genomic coordinate). No such comparator was identified for c.301 in the available evidence. Details ▾Hide ▴
Still missing
  • No pathogenic comparator at NM_000143.4:c.301 identified
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a different nucleotide change at the same codon produces the same missense amino acid change that is already established as pathogenic. This variant is a nonsense (stop-gain) change, not a missense variant, so PS1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. FH-associated HLRCC is an autosomal dominant disorder, so PM3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in a non-repeat region or stop-loss variants that alter protein length. This is a nonsense (stop-gain) variant creating a truncated protein, not an in-frame change or stop-loss variant, so PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different missense change has been determined to be pathogenic. This is a nonsense variant (R101*), not a missense change. Automated PM5 candidate harvesting was unable to identify eligible same-residue comparators under classic PM5 semantics. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvesting returned no eligible comparators for this nonsense variant
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in a gene with a low rate of benign missense variation (high missense constraint). This is a nonsense (truncating) variant, not a missense variant, so PP2 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a nonsense (truncating) variant, so BP1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in a repetitive region without a known function. This is a single-nucleotide substitution resulting in a nonsense change, so BP3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or splicing efficiency. This variant is a nonsense (stop-gain) change, not a synonymous variant, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
FH
Transcript
NM_000143.4
Coding (HGVS c.)
NM_000143.4:c.301C>T
Protein (HGVS p.)
NP_000134.2:p.(Arg101Ter)
GRCh38
chr1:241513680 G>A
GRCh37
chr1:241676980 G>A
ClinVar
16232

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…
gnomAD v4.1 12 / 1,613,900 alleles AF 7.44e-06 · 0 homozygotes · FAF 5.42e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 7.4e-06 · 12 / 1,613,900 alleles · 0 hom · FAF 5.4e-06
European (non-Finnish)12 / 1,179,948 1e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 7.4354e-06; MAF= 0.00074%, 12/1613900 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.01699e-05; MAF= 0.00102%, 12/1179948 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +33 bp
0.000
SpliceAI acceptor gainat +26 bp
0.000
SpliceAI donor lossat -77 bp
0.000
SpliceAI donor gainat -84 bp
0.000
Pangolin splice lossmagnitude shown
-0.040
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.486

How the predictions were used

PP3 Insufficient computational evidence to support a deleterious effect. SpliceAI predicts no splice-altering impact (max delta score = 0.00). BayesDel score is borderline at 0.486, below typical deleterious thresholds. REVEL is unavailable for this variant. No multiple lines of in silico evidence converge on a deleterious prediction to satisfy PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00 (no splice impact predicted)
  • BayesDel: score 0.486 (borderline
  • not in damaging range)
  • REVEL: not available for this variant
Sources
spliceai ↗bayesdel
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI predicts no splice impact (max delta = 0.00), which is one line of non-damaging evidence. However, BayesDel is borderline (0.486) and REVEL is unavailable, so there are not multiple lines of computational evidence converging on a benign prediction. A single non-damaging SpliceAI score is insufficient for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.00 (no splice impact)
  • BayesDel: 0.486 (borderline
  • not conclusive for benign)
  • REVEL: not available
  • Only one clear line of benign computational evidence — insufficient for BP4
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or splicing efficiency. This variant is a nonsense (stop-gain) change, not a synonymous variant, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.486496.

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
    Tomlinson IP et al. · 2002
    No paper-specific finding is recorded.
    PMID 11865300 ↗
  • Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.
    Wei MH et al. · 2006
    No paper-specific finding is recorded.
    PMID 15937070 ↗
  • Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
    No paper-specific finding is recorded.
    PMID 12761039 ↗
  • Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
    No paper-specific finding is recorded.
    PMID 12772087 ↗
  • Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer.
    Pithukpakorn M et al. · 2006
    No paper-specific finding is recorded.
    PMID 16597677 ↗
  • Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.
    Gardie B et al. · 2011
    No paper-specific finding is recorded.
    PMID 21398687 ↗
  • 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 12 / 1,613,900 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 14 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

This variant is present in gnomAD v4.1 (AF= 7.4354e-06; MAF= 0.00074%, 12/1613900 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.01699e-05; MAF= 0.00102%, 12/1179948 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories). (ClinVarID = 16232)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.486496.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.