Classification rationale

PM2PP3 VUS

FH c.1366G>T

The FH c.1366G>T (p.Val456Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.¹ 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.² 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).³

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

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.

Gene diagram · NM_000143.4 · variants mapped to exon structure

FH NM_000143.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

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.

gnomAD v2.1 total AF 3.18492e-05gnomAD v4.1 total AF 1.85872e-06

gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting review Pathogenic

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.

REVEL score 0.913BayesDel score 0.286106SpliceAI max delta score 0.00

spliceai ↗

Assessed · not applied · 4 not met · 16 not assessed

Pathogenic

PS1 No established pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available evidence.

PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant.

PS3 No well-established functional study demonstrating a damaging effect of this specific variant was identified.

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.

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.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.

PM5 No confirmed pathogenic or likely pathogenic missense comparator at the same residue was available for use, so PM5 was not applied.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified showing this variant tracking with disease in affected relatives.

PP2 Available evidence did not establish a gene-specific disease mechanism pattern that would support PP2 for this missense variant.

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.

Benign

BA1 Population frequency does not meet the BA1 threshold.

BS1 Population frequency does not meet the BS1 threshold.

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.

BS3 No well-established functional study demonstrating normal function of this specific variant was identified.

BS4 No non-segregation data were identified showing that this variant fails to track with disease in informative families.

BP1 Available evidence did not establish a gene-specific pattern showing that benign interpretation is favored for missense variants in FH.

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.

BP4 Available computational evidence does not support a benign effect.

BP5 No evidence was identified for an alternate molecular cause that would explain the phenotype independently of this variant.

N/A · 6 PVS1 · PM4 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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).

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).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,014
0 hom

European (Finnish)

3 / 64,022

0.0047%

+ 9 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0032% · 1 / 31,398
0 hom

European (Finnish)

1 / 3,476

0.029%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4257325)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.286106.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

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. CLINVAR

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