Variant classification summary

NM_000143.4:c.1127A>C

FH · NP_000134.2:p.(Gln376Pro) · NM_000143.4

GRCh37: chr1:241665852 T>G · GRCh38: chr1:241502552 T>G

Gene: FH Transcript: NM_000143.4

Final call

VUS

PS3 supporting PM1 supporting PM2 supporting PP3 supporting

Variant details

Gene

FH

Transcript

NM_000143.4

Protein

NP_000134.2:p.(Gln376Pro)

gnomAD AF

4.646730746116262e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000143.4:c.1127A>C (p.Gln376Pro) is a missense variant in the fumarate lyase domain of FH, a critical catalytic region where pathogenic missense variants cluster.

2

This variant is absent from gnomAD-Canada and present at very low frequency in gnomAD v2.1 (AF=0.00601%, 17/282,834 alleles) and v4.1 (AF=0.00465%, 75/1,614,038 alleles), with no homozygotes observed.

3

REVEL (0.97) and BayesDel (0.565) in silico predictors support a deleterious effect; SpliceAI predicts no splicing impact (max delta 0.00).

4

Remes et al. (2004) identified c.1127A>C as a novel pathogenic mutation in a family with autosomal recessive fumarase deficiency, confirming variant-specific functional relevance.

5

ClinVar classifies this variant as Pathogenic (2-star, criteria provided by single submitter) with 7 clinical laboratories reporting Pathogenic, 2 Likely pathogenic, 2 VUS, and 1 likely pathogenic.

6

Met criteria: PM1 (supporting, fumarate lyase domain), PM2 (supporting, low population frequency), PP3 (supporting, in silico predictors), PS3 (supporting, functional study). Total: 4 supporting pathogenic criteria. No benign criteria met.

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	NM_000143.4:c.1127A>C is a missense variant (p.Gln376Pro) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence available of a different nucleotide change at codon 376 resulting in the same amino acid substitution (p.Gln376Pro).
PS2	N/A	No de novo report for NM_000143.4:c.1127A>C identified in any case materials.
PS3	Met	NM_000143.4:c.1127A>C was identified as a novel pathogenic mutation in the fumarase gene by Remes et al. (2004, PMID:15221078). The abstract confirms the variant was directly studied; however, full-text functional assay data are not available for independent confirmation. A single publication with abstract-level variant-specific evidence supports PS3 at supporting strength.	PMID:15221078
PS4	Not assessed	The variant is reported in multiple ClinVar submissions (7 Pathogenic, 2 Likely pathogenic, 2 VUS, 1 likely pathogenic) but no formal case-control study or statistically powered enrichment analysis in affected versus unaffected populations is available in the case materials.	clinvar
PS5	Not met	No same-residue pathogenic missense comparator was identified at codon 376. The pm5_candidates collection found zero eligible same-residue comparator variants.	pm5_candidates
PM1	Met	NM_000143.4:c.1127A>C (p.Gln376Pro) is located in the fumarate lyase domain of FH, a critical functional domain where pathogenic missense variants cluster. Large-scale profiling studies confirm exons 5-7 in this domain as predominant mutational hotspots in hereditary FH-deficient disease.	PMID:15221078
PM2	Met	This variant is absent from gnomAD-Canada and present at very low frequency: gnomAD v2.1 AF=0.00601% (17/282,834 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.00465% (75/1,614,038 alleles, 0 homozygotes), both well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no pathogenic comparator variants at codon 376 were identified in the candidate search.	pm5_candidates
PM6	N/A	No de novo report for this variant identified in any case materials.
PP1	Not assessed	No cosegregation data available in the case materials.
PP2	Not assessed	No missense constraint metric (e.g., Z-score, pLI, missense o/e) is available for the FH gene in the case materials.
PP3	Met	Multiple in silico predictors support a deleterious effect: REVEL score 0.97 (strongly pathogenic) and BayesDel score 0.565 (damaging prediction). SpliceAI predicts no splice impact (max delta 0.00).	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype data or clinical history is available in the case materials.
PP5	Not met	ClinVar classifies this variant as Pathogenic with review status 'criteria provided, single submitter' (2-star). The PP5 threshold requires 3-star expert panel review status; this variant does not meet that threshold.	clinvar
BA1	Not met	The variant has an allele frequency of 0.006% (gnomAD v2.1), 0.0047% (gnomAD v4.1), far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant has an allele frequency of 0.006% (gnomAD v2.1), far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	While the variant is observed in gnomAD (17 alleles in v2.1, 75 in v4.1), HLRCC is an adult-onset dominant condition and gnomAD individuals cannot be confirmed as unaffected. Observation in a population database does not constitute observation in a confirmed healthy adult for this disorder.	gnomad_v2 gnomad_v4
BS3	Not met	The only functional study identified (PMID 15221078) characterizes this variant as a novel pathogenic mutation associated with fumarase deficiency, not as a benign variant. No evidence supports a benign functional effect.	PMID:15221078
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease.
BP1	Not met	FH-related disorders (HLRCC and fumarase deficiency) are caused by both missense and truncating variants. Missense variants in the fumarate lyase domain are an established mechanism of pathogenicity.	PMID:15221078
BP2	N/A	FH has a complex inheritance pattern with both autosomal recessive (fumarase deficiency) and autosomal dominant (HLRCC) disease associations. Observation in trans with a pathogenic variant cannot be simply interpreted.
BP4	Not met	REVEL score 0.97 and BayesDel score 0.565 both predict a damaging effect, not a benign one. Multiple lines of computational evidence support pathogenicity.	revel bayesdel spliceai
BP5	Not assessed	No data indicating this variant was found in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Pathogenic, not benign. BP6 is not applicable.	clinvar
BP7	N/A	NM_000143.4:c.1127A>C is a missense variant (p.Gln376Pro), not a synonymous variant.
BP3	N/A	Skipped per instruction: in-frame indel criterion, not applicable to this missense substitution.
PM3	N/A	Skipped per instruction: trans observation criterion for recessive disorders; no trans data assessed.
PM4	N/A	Skipped per instruction: protein length change criterion; this is a missense substitution, not an in-frame indel or stop-loss.

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