NM_000143.4:c.1366G>T

FH · NP_000134.2:p.(Val456Leu) · NM_000143.4

GRCh37: chr1:241663761 C>A · GRCh38: chr1:241500461 C>A

Gene: FH Transcript: NM_000143.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

Transcript

NM_000143.4

Protein

NP_000134.2:p.(Val456Leu)

gnomAD AF

1.8587199367539563e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	FH 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No established pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available evidence.
PS2	Not assessed	No de novo occurrence with confirmed maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this specific variant was identified.	oncokb
PS4	Not assessed	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.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	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.	hotspots
PM2	Met	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 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.	clinvar
PM4	N/A	This is a missense substitution and does not change protein length, so PM4 is not applicable.
PM5	Not assessed	No confirmed pathogenic or likely pathogenic missense comparator at the same residue was available for use, so PM5 was not applied.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified showing this variant tracking with disease in affected relatives.	clinvar
PP2	Not assessed	Available evidence did not establish a gene-specific disease mechanism pattern that would support PP2 for this missense variant.
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	No case-level phenotype data were identified showing a clinical presentation highly specific for an FH-related disorder in an individual carrying this variant.	clinvar
PP5	N/A	Assertion-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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	Available population data do not show this variant in a number of healthy individuals sufficient to support BS2; no homozygotes were reported in gnomAD.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating normal function of this specific variant was identified.	oncokb
BS4	Not assessed	No non-segregation data were identified showing that this variant fails to track with disease in informative families.	clinvar
BP1	Not assessed	Available evidence did not establish a gene-specific pattern showing that benign interpretation is favored for missense variants in FH.
BP2	Not assessed	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.	clinvar
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable.
BP4	Not met	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).	revel bayesdel spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular cause that would explain the phenotype independently of this variant.
BP6	N/A	Assertion-only benign classification evidence was not used for BP6, and no reputable benign classification without available supporting evidence was identified.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable.

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