Submissions for variant NM_000143.4(FH):c.7C>G (p.Arg3Gly)

gnomAD frequency: 0.00022  dbSNP: rs202166344

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195609	SCV000251490	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195609	SCV000262348	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000204400	SCV000356748	uncertain significance	Fumarase deficiency	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346414	SCV000356749	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346414	SCV000356750	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568788	SCV000673354	likely benign	Hereditary cancer-predisposing syndrome	2020-09-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV001818470	SCV002071328	uncertain significance	not specified	2019-10-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818470	SCV002552161	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000346414	SCV003928154	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2023-04-20	criteria provided, single submitter	clinical testing	The FH c.7C>G (p.Arg3Gly) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000204400	SCV004197311	uncertain significance	Fumarase deficiency	2024-03-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000195609	SCV005331221	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FH: PM2
Natera, Inc.	RCV000204400	SCV001458394	uncertain significance	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734852	SCV005356361	uncertain significance	FH-related disorder	2024-03-26	no assertion criteria provided	clinical testing	The FH c.7C>G variant is predicted to result in the amino acid substitution p.Arg3Gly. In a large cohort study on the association between germline variants in fumarate hydratase (FH) and hereditary cancers such as leiomyomatosis, renal cell cancer (HLRCC), paraganglioma (PGL) and pheochromocytoma (PCC), this variant has been reported in an individual with PGL/PCC (Table 2. Zavoshi et al 2023. PMID: 36773955). This variant is reported in 0.019% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/214430/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.