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.1 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.2 REVEL (0.97) and BayesDel (0.565) in silico predictors support a deleterious effect; SpliceAI predicts no splicing impact (max delta 0.00).3 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.4 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.5 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.
FH
Final classification
VUS
FH c.1127A>C · p.Gln376Pro
FH
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 supporting, PM1 supporting, PM2 supporting, PP3 supporting; combination = 4 supporting, which maps to VUS.
Classification rationale
PS3PM1PM2PP3
VUS
FH c.1127A>C
PS3 + PM1 + PM2 + PP3
→
VUS
3
revelbayesdelspliceai ↗
Gene diagram
· NM_000143.4 · variants mapped to exon structure
FH
NM_000143.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 15 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
supporting
review
Pathogenic
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 abstract confirms identification of c.1127A>C as a novel mutation in a family with autosomal recessive fumarase deficiencyfunctional characterization described.
✓
PM1
supporting
Pathogenic
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.
Position 376 lies within the fumarate lyase domaina critical catalytic domain of FHPMID 15221078 describes this region as functionally important in fumarase deficiency.
✓
PM2
supporting
Pathogenic
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 v2.1: AF=0.00601% (17/282834)0 homozygotes
✓
PP3
supporting
Pathogenic
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: 0.97 (pathogenic range)BayesDel: 0.565 (damaging)SpliceAI: max delta 0.00 (no splice impact)
Assessed · not applied
Pathogenic
PS1
No evidence available of a different nucleotide change at codon 376 resulting in the same amino acid substitution (p.Gln376Pro).
PS4
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.
PP1
No cosegregation data available in the case materials.
PP2
No missense constraint metric (e.g., Z-score, pLI, missense o/e) is available for the FH gene in the case materials.
PP4
No patient-specific phenotype data or clinical history is available in the case materials.
PP5
ClinVar classifies this variant as Pathogenic with review status 'criteria provided, single submitter' (2-star).
Benign
BA1
The variant has an allele frequency of 0.006% (gnomAD v2.1), 0.0047% (gnomAD v4.1), far below the BA1 threshold of >1%.
BS1
The variant has an allele frequency of 0.006% (gnomAD v2.1), far below the BS1 threshold of >0.3%.
BS2
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.
BS3
The only functional study identified (PMID 15221078) characterizes this variant as a novel pathogenic mutation associated with fumarase deficiency, not as a benign variant.
BS4
No segregation data available to assess lack of cosegregation with disease.
BP1
FH-related disorders (HLRCC and fumarase deficiency) are caused by both missense and truncating variants.
BP4
REVEL score 0.97 and BayesDel score 0.565 both predict a damaging effect, not a benign one.
BP5
No data indicating this variant was found in a case with an alternate molecular basis for disease.
BP6
ClinVar classifies this variant as Pathogenic, not benign.
N/A · 9
PVS1 · PS2 · PM3 · PM4 · PM5 · PM6 · BP2 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.64673e-05; MAF= 0.00465%, 75/1614038 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000156167; MAF= 0.01562%, 10/64034 alleles, homozygotes = 0); grpmax FAF= 4.182e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.01059e-05; MAF= 0.00601%, 17/282834 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000108389; MAF= 0.01084%, 14/129164 alleles, homozygotes = 0); grpmax FAF= 6.663e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0046%
· 75 / 1,614,038
0 hom · FAF 0.0042%
0 hom · FAF 0.0042%
European (Finnish) 10 / 64,034 |
0.016% |
European (non-Finnish) 62 / 1,180,012 |
0.0053% |
African/African American 2 / 74,940 |
0.0027% |
Remaining individuals 1 / 62,488 |
0.0016% |
+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.006%
· 17 / 282,834
0 hom · FAF 0.0067%
0 hom · FAF 0.0067%
European (non-Finnish) 14 / 129,164 |
0.011% |
European (Finnish) 2 / 25,124 |
0.008% |
African/African American 1 / 24,972 |
0.004% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as likely pathogenic (1 clinical laboratory). (ClinVarID = 42094)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.97. BayesDel score = 0.565222.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105921172, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency.
Searched
c.1127A>Cp.Gln376ProQ376P1127A>C
Found
Remes et al. describe a novel mutation at nucleotide 1127A>C of the fumarase gene in a family with autosomal recessive fumarase deficiency. The variant was identified as a pathogenic mutation associated with loss of fumarase activity.
Variant
✓ Names this variant
Applied to
→PM1 supports · met
→PS3 supports · met
Why
Variant-specific functional evidence confirmed at abstract level; cited for PS3 (supporting) and PM1 (supporting, domain). Full text not available for detailed functional assay confirmation.
We describe a novel mutation in nucleotide 1127A>C of the fumarase gene
Location Abstract
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
17182618 ↗
Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.
CLINVAR
19151755 ↗
Downregulation of SRF-FOS-JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
37255402 ↗
FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.
CLINVAR
10896297 ↗
Abnormalities in succinylpurines in fumarase deficiency: possible role in pathogenesis of CNS impairment.
CLINVAR