About FH
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FH c.1366G>T, p.(Val456Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is rare in population databases, with gnomAD v2.1 AF 3.18492e-05 (0.00318%, 1/31,398 alleles) and gnomAD v4.1 AF 1.85872e-06 (0.00019%, 3/1,614,014 alleles), both below the 0.1% PM2 threshold.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious protein effect for this missense change, with REVEL 0.913 and BayesDel 0.286106, while SpliceAI predicts no significant splice impact (max delta score 0.00). Overall, the in silico results support pathogenicity through a missense mechanism rather than a splicing mechanism.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
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
3 / 1,614,014 alleles
gnomAD v4.1: 3 / 1,614,014 alleles. Recorded AF 1.85872e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18492e-05; MAF= 0.00318%, 1/31398 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000287687; MAF= 0.02877%, 1/3476 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
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.
No listed criterion applied
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The FH c.1366G>T (p.Val456Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.
This variant is rare in population databases, with gnomAD v2.1 AF 0.00318% (1/31,398 alleles) and gnomAD v4.1 AF 0.00019% (3/1,614,014 alleles), which are both below the 0.1% PM2 threshold and well below the BS1 and BA1 frequency thresholds.
Computational evidence supports a deleterious missense effect, with REVEL 0.913 and BayesDel 0.286106, while SpliceAI predicts no significant splice impact for this variant (max delta score 0.00).
No criteria match.
Met · 2
PM2 SupportingThis variant is rare in population databases, with gnomAD v2.1 AF 3.18492e-05 (0.00318%, 1/31,398 alleles) and gnomAD v4.1 AF 1.85872e-06 (0.00019%, 3/1,614,014 alleles), both below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 3.18492e-05
- gnomAD v4.1 total AF 1.85872e-06
Sources
PP3 SupportingComputational evidence supports a deleterious protein effect for this missense change, with REVEL 0.913 and BayesDel 0.286106, while SpliceAI predicts no significant splice impact (max delta score 0.00). Overall, the in silico results support pathogenicity through a missense mechanism rather than a splicing mechanism. Details ▾Hide ▴
Evidence considered
- REVEL score 0.913
- BayesDel score 0.286106
- SpliceAI max delta score 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Available evidence does not support this residue as a mutational hotspot or other well-established critical region without benign variation; Cancer Hotspots did not identify a statistically significant hotspot at codon 456. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review did not show a significant hotspot row for FH V456
Still missing
- No independently established critical functional-domain evidence for codon 456 was identified.
Sources
BA1 Population frequency does not meet the BA1 threshold. The highest observed population frequency was 0.02877% in gnomAD v2.1 Finnish and 0.00469% in gnomAD v4.1 Finnish, both well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Highest observed gnomAD v2.1 subgroup AF 0.000287687
- Highest observed gnomAD v4.1 subgroup AF 4.68589e-05
Sources
BS1 Population frequency does not meet the BS1 threshold. The highest observed population frequency was 0.02877% in gnomAD v2.1 Finnish and 0.00469% in gnomAD v4.1 Finnish, both below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Highest observed gnomAD v2.1 subgroup AF 0.000287687
- Highest observed gnomAD v4.1 subgroup AF 4.68589e-05
Sources
BP4 Available computational evidence does not support a benign effect. REVEL 0.913 and BayesDel 0.286106 support a damaging missense effect, although SpliceAI predicts no significant splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL score 0.913
- BayesDel score 0.286106
- SpliceAI max delta score 0.00
Sources
Not assessed · 16 · no assessment recorded
PS1 No established pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available evidence. Details ▾Hide ▴
Still missing
- No confirmed same-amino-acid pathogenic comparator was available for review.
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar shows a single submitter record without de novo evidence
Still missing
- No published or database-supported confirmed de novo case was identified.
Sources
PS3 No well-established functional study demonstrating a damaging effect of this specific variant was identified. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No validated variant-specific functional assay result was available.
Sources
PS4 This variant has been reported in ClinVar, but no case-control or clear affected-versus-control enrichment data were identified to show increased prevalence in affected individuals. Details ▾Hide ▴
Evidence considered
- ClinVar contains one single-submitter VUS record
- gnomAD shows rare population presence
Still missing
- No published enrichment study or multiple well-documented affected probands were identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Evidence considered
- No trans configuration data were available in the reviewed materials
Still missing
- No phase-confirmed trans observations were identified.
Sources
PM5 No confirmed pathogenic or likely pathogenic missense comparator at the same residue was available for use, so PM5 was not applied. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found no usable same-residue comparator
Still missing
- No reviewed same-residue pathogenic comparator was identified.
Sources
pm5_candidates
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo wording was available in the reviewed ClinVar evidence
Still missing
- No presumed de novo case description was identified.
Sources
PP1 No segregation data were identified showing this variant tracking with disease in affected relatives. Details ▾Hide ▴
Evidence considered
- No segregation information was available in the reviewed materials
Still missing
- No family segregation study or pedigree data were identified.
Sources
PP2 Available evidence did not establish a gene-specific disease mechanism pattern that would support PP2 for this missense variant. Details ▾Hide ▴
Still missing
- No reviewed gene-level missense-versus-truncating constraint framework was available for PP2.
PP4 No case-level phenotype data were identified showing a clinical presentation highly specific for an FH-related disorder in an individual carrying this variant. Details ▾Hide ▴
Evidence considered
- ClinVar record does not provide phenotype-specific evidence sufficient for PP4
Still missing
- No phenotype-rich case report or laboratory submission details were identified.
Sources
BS2 Available population data do not show this variant in a number of healthy individuals sufficient to support BS2; no homozygotes were reported in gnomAD. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD v2.1
- Zero homozygotes in gnomAD v4.1
Still missing
- No healthy adult cohort evidence sufficient for BS2 was identified.
Sources
BS3 No well-established functional study demonstrating normal function of this specific variant was identified. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No validated benign-supporting functional assay result was available.
Sources
BS4 No non-segregation data were identified showing that this variant fails to track with disease in informative families. Details ▾Hide ▴
Evidence considered
- No family-based non-segregation evidence was available in the reviewed materials
Still missing
- No family non-segregation evidence was identified.
Sources
BP1 Available evidence did not establish a gene-specific pattern showing that benign interpretation is favored for missense variants in FH. Details ▾Hide ▴
Still missing
- No reviewed gene-level evidence supporting BP1 was identified.
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a manner supporting BP2. Details ▾Hide ▴
Evidence considered
- No co-occurrence data were available in the reviewed materials
Still missing
- No phasing or co-occurrence data were identified.
Sources
BP5 No evidence was identified for an alternate molecular cause that would explain the phenotype independently of this variant. Details ▾Hide ▴
Still missing
- No case-level alternate-cause evaluation was available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AFH loss of function is an established disease mechanism, but this variant is a missense change, NM_000143.4:c.1366G>T (p.Val456Leu), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Details ▾Hide ▴
Evidence considered
- FH is eligible for generic PVS1 framework review at the gene level
- Variant-level PVS1 scaffold indicates this missense change is outside default null-variant buckets
Sources
PM4 N/AThis is a missense substitution and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Val456Leu
PP5 N/AAssertion-only classification evidence was not used for PP5. ClinVar contains a single submitter classification of uncertain significance, which does not support pathogenic assertion-based weighting. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is a missense substitution
BP6 N/AAssertion-only benign classification evidence was not used for BP6, and no reputable benign classification without available supporting evidence was identified. Details ▾Hide ▴
Evidence considered
- ClinVar contains a single VUS submission rather than a benign assertion
Sources
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Val456Leu
Identifiers
- Gene
- FH
- Transcript
- NM_000143.4
- Coding (HGVS c.)
- NM_000143.4:c.1366G>T
- Protein (HGVS p.)
- NP_000134.2:p.(Val456Leu)
- GRCh38
- chr1:241500461 C>A
- GRCh37
- chr1:241663761 C>A
- ClinVar
- 4257325
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3 / 1,614,014 alleles
AF 1.86e-06 · 0 homozygotes
gnomAD v2.1
1 / 31,398 alleles
AF 3.18e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,014 alleles · 0 hom
| European (Finnish)3 / 64,022 | 4.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 3.2e-05 · 1 / 31,398 alleles · 0 hom
| European (Finnish)1 / 3,476 | 0.00029 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85872e-06; MAF= 0.00019%, 3/1614014 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.68589e-05; MAF= 0.00469%, 3/64022 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18492e-05; MAF= 0.00318%, 1/31398 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000287687; MAF= 0.02877%, 1/3476 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.913
- BayesDel
- 0.286
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious protein effect for this missense change, with REVEL 0.913 and BayesDel 0.286106, while SpliceAI predicts no significant splice impact (max delta score 0.00). Overall, the in silico results support pathogenicity through a missense mechanism rather than a splicing mechanism. Details ▾Hide ▴
Evidence considered
- REVEL score 0.913
- BayesDel score 0.286106
- SpliceAI max delta score 0.00
Sources
BP4 Available computational evidence does not support a benign effect. REVEL 0.913 and BayesDel 0.286106 support a damaging missense effect, although SpliceAI predicts no significant splice impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL score 0.913
- BayesDel score 0.286106
- SpliceAI max delta score 0.00
Sources
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Val456Leu
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.286106.
1 paper record 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
-
PMID 25394175 ↗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.Hampel H et al. · 2015No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,614,014 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
1 Uncertain significance
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/4257325/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-241663761-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-241500461-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000143.4%3Ac.1366…
- OncoKB ↗www.oncokb.org/gene/FH/V456L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FH+c.1366G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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= 1.85872e-06; MAF= 0.00019%, 3/1614014 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.68589e-05; MAF= 0.00469%, 3/64022 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18492e-05; MAF= 0.00318%, 1/31398 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000287687; MAF= 0.02877%, 1/3476 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4257325)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.286106.
Functional
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.
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.