Submissions for variant NM_000143.4(FH):c.415G>A (p.Val139Met)

gnomAD frequency: 0.00001  dbSNP: rs200343823

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001585739	SCV000950513	uncertain significance	not provided	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 139 of the FH protein (p.Val139Met). This variant is present in population databases (rs200343823, gnomAD 0.03%). This missense change has been observed in individual(s) with renal cancer (PMID: 30548481). This missense change has been observed to be homozygous, hemizygous or homoplasmic in an individual who did not have the expected clinical features for that genetic result (internal data). ClinVar contains an entry for this variant (Variation ID: 654367). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001021974	SCV001183656	likely benign	Hereditary cancer-predisposing syndrome	2022-12-22	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.
Illumina Laboratory Services, Illumina	RCV000810319	SCV001257306	uncertain significance	Fumarase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100769	SCV001257307	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001585739	SCV001821110	uncertain significance	not provided	2024-10-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30548481)
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153850	SCV003843732	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000810319	SCV004197352	uncertain significance	Fumarase deficiency	2023-06-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001585739	SCV004218881	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00025 (5/19944 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with renal cancer (PMID: 30548481 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV001100769	SCV005407524	likely benign	Hereditary leiomyomatosis and renal cell cancer	2024-08-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252807	SCV001163950	uncertain significance	Microcephaly		no assertion criteria provided	research
Natera, Inc.	RCV000810319	SCV001458381	uncertain significance	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing