Submissions for variant NM_000143.4(FH):c.1127A>C (p.Gln376Pro)

gnomAD frequency: 0.00005  dbSNP: rs200796606

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163798	SCV000214379	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-19	criteria provided, single submitter	clinical testing	The p.Q376P variant (also known as c.1127A>C), located in coding exon 8 of the FH gene, results from an A to C substitution at nucleotide position 1127. The glutamine at codon 376 is replaced by proline, an amino acid with similar properties. This alteration has been identified in a homozygous state or in conjunction with other FH alterations in individuals affected with autosomal recessive FH deficiency and was found to segregate with disease in siblings from these families (Remes AM et al. J. Mol. Med., 2004 Aug;82:550-4; Phillips TM et al. Pediatr. Neurol., 2006 Aug;35:150-3; Zeman J et al. J. Inherit. Metab. Dis., 2000 Jun;23:371-4; Chan MMY et al. BMC Med. Genet., 2017 07;18:79). In the cases where parents of these children who carried this alteration were ascertained for autosomal dominant HLRCC no evidence of uterine or dermal leiomyomas or renal manifestations were identified, despite half the normal fumarate hydratase activity in their blood mononuclear cells (Remes AM et al. J. Mol. Med., 2004 Aug;82:550-4; Chan MMY et al. BMC Med. Genet., 2017 07;18:79; Zeman J et al. J. Inherit. Metab. Dis., 2000 Jun;23:371-4). Cells derived from a homozygous patient showed other cellular anomalies including abnormal protein profiles, FH cellular localization, and cellular growth (Raimundo N et al. Biochim. Biophys. Acta, 2008 May;1782:287-94; Raimundo N et al. Oncogene, 2009 Mar;28:1261-73). This alteration lies withing a core helix and is predicted to affect subunit interactions and the structural integrity of the protein (Picaud S et al. J. Inherit. Metab. Dis., 2011 Jun;34:671-6; Ambry internal data). Of note, this alteration is also designated as c.998A>C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is expected to be causative of autosomal recessive FH deficiency when present along with a second likely pathogenic/ pathogenic variant on the other allele; however, the clinical significance for autosomal dominiant HLRCC is unclear.
GeneDx	RCV000199873	SCV000251429	pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	Observed in either the homozygous state or in trans with another FH variant in individuals with fumarate hydratase (FH) deficiency referred for genetic testing at GeneDx and in the literature; however the parents and other heterozygous relatives of these individuals were not reported as having features of hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 10896297, 15221078, 16876016, 28747166); Studies suggest that in the heterozygous state, this variant is not associated with an increased risk to develop HLRCC-related tumors; however, there have been recent reports of this variant observed in individuals with history of renal cell carcinoma and/or pheochromocytomas (PMID: 18366737, 34994643, 34439371, 35971132, 35441217); Published functional studies demonstrate a damaging effect: the variant abolishes enzymatic activity and disrupts FH tetramerization (PMID: 37255402); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 998A>C, Gln333Pro, and Gln13Pro; This variant is associated with the following publications: (PMID: 19151755, 25637381, 21445611, 15221078, 17182618, 18313410, 20549362, 10896297, 28747166, 16155190, 20301679, 18366737, 35971132, 34439371, 35441217, 36612198, 34994643, 16876016, 36672771, 23210851, 37255402)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199873	SCV000632435	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 376 of the FH protein (p.Gln376Pro). This variant is present in population databases (rs200796606, gnomAD 0.01%). This missense change has been observed in individual(s) with fumarate hydratase deficiency (FHD) (PMID: 10896297, 15221078, 16876016, 28747166). It has also been observed to segregate with disease in related individuals. This variant is also known as 998A>C, Gln13Pro, and Gln333Pro. ClinVar contains an entry for this variant (Variation ID: 42094). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 17182618, 18313410). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000034920	SCV001428576	likely pathogenic	Fumarase deficiency	2017-10-05	criteria provided, single submitter	clinical testing	This variant was identified as homozygous
Revvity Omics, Revvity	RCV000199873	SCV002022985	pathogenic	not provided	2019-04-11	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004595492	SCV003928116	pathogenic	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2023-04-20	criteria provided, single submitter	clinical testing	The FH c.1127A>C (p.Gln376Pro) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and a crystal structure study predicted this alteration affects protein interaction and structural integrity (PMID: 21445611). Functional studies have shown that this missense change affects FH function in the homozygous state (PMID: 18313410, 19151755). This variant has been identified in individuals with fumarase deficiency in the homozygous and compound heterozygous state (PMID: 10896297, 15221078, 16876016, 28747166). It has also been reported in individuals with features of HLRCC (PMID: 28747166, 35441217). This variant is also known as 998A>C, Gln13Pro, and Gln333Pro. Based on the available evidence, this variant is classified as a pathogenic mutation in association with fumarase deficiency when in the homozygous or compound heterozygous state; however, the clinical significance with respect to the cancer predisposition syndrome hereditary leiomyomatosis and renal cell cancer remains unclear.
Baylor Genetics	RCV000034920	SCV004197296	pathogenic	Fumarase deficiency	2024-03-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV004595492	SCV005640073	pathogenic	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2024-05-07	criteria provided, single submitter	clinical testing
GeneReviews	RCV000034920	SCV000058527	not provided	Fumarase deficiency		no assertion provided	literature only
CSER _CC_NCGL, University of Washington	RCV000034920	SCV000190211	likely benign	Fumarase deficiency	2014-06-01	flagged submission	research
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000199873	SCV002010137	uncertain significance	not provided	2021-11-03	flagged submission	clinical testing
CZECANCA consortium	RCV002280864	SCV002569171	likely pathogenic	Hepatocellular carcinoma	2022-05-17	no assertion criteria provided	case-control