ClinVar Miner

Submissions for variant NM_000143.4(FH):c.1303G>A (p.Val435Met)

gnomAD frequency: 0.00021  dbSNP: rs147528200
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001564388 SCV000544282 uncertain significance not provided 2022-11-01 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 435 of the FH protein (p.Val435Met). This variant is present in population databases (rs147528200, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 134418). 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. 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 RCV000571469 SCV000673360 likely benign Hereditary cancer-predisposing syndrome 2022-04-26 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.
GeneDx RCV001564388 SCV001787547 uncertain significance not provided 2023-10-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer or endocrine tumors as well as unaffected controls (PMID: 24728327, 29684080, 32808982, 32008151); This variant is associated with the following publications: (PMID: 32008151, 32561076, 25004247, 29641532, 24728327, 27377421, 29684080, 32808982, 37569332)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000121094 SCV004025209 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003325184 SCV004031172 uncertain significance Hereditary leiomyomatosis and renal cell cancer 2023-05-31 criteria provided, single submitter clinical testing The FH c.1303G>A (p.Val435Met) missense change has a maximum subpopulation frequency of 0.06% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) or fumarase deficiency. 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.
PreventionGenetics, part of Exact Sciences RCV004555537 SCV004114474 uncertain significance FH-related disorder 2023-12-29 criteria provided, single submitter clinical testing The FH c.1303G>A variant is predicted to result in the amino acid substitution p.Val435Met. This variant has been reported as a germline variant in patient with Cushing syndrome due to bilateral adrenocortical hyperplasia or adenoma (Berthon et al. 2020. PubMed ID: 32808982). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-241663824-C-T) and has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134418/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001564388 SCV004218871 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000473170 SCV005057744 uncertain significance Fumarase deficiency 2024-03-22 criteria provided, single submitter clinical testing
ITMI RCV000121094 SCV000085262 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000473170 SCV001457337 uncertain significance Fumarase deficiency 2020-09-16 no assertion criteria provided clinical testing

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