Submissions for variant NM_004168.4(SDHA):c.1591G>A (p.Val531Met)

gnomAD frequency: 0.00009  dbSNP: rs371056571

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193391	SCV000248837	uncertain significance	not specified	2015-07-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226464	SCV000288118	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2025-01-23	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 531 of the SDHA protein (p.Val531Met). This variant is present in population databases (rs371056571, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 212143). 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 not expected to disrupt SDHA protein function with a negative 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.
Counsyl	RCV000410380	SCV000488010	uncertain significance	Paragangliomas 5	2015-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573905	SCV000674957	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The p.V531M variant (also known as c.1591G>A), located in coding exon 12 of the SDHA gene, results from a G to A substitution at nucleotide position 1591. The valine at codon 531 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001093473	SCV001829286	uncertain significance	not provided	2024-04-19	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in a pediatric patient with an unspecified cancer (PMID: 30455982); This variant is associated with the following publications: (PMID: 30455982)
Sema4, Sema4	RCV000573905	SCV002527725	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410380	SCV004045351	uncertain significance	Paragangliomas 5	2023-04-24	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV004567397	SCV005056594	uncertain significance	Dilated cardiomyopathy 1GG	2023-11-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001093473	SCV005410660	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001093473	SCV005624086	uncertain significance	not provided	2024-02-26	criteria provided, single submitter	clinical testing	The SDHA c.1591G>A (p.Val531Met) variant has been reported in the published literature in an individual affected with a pediatric tumor (PMID: 30455982 (2018)). The frequency of this variant in the general population, 0.00044 (11/24966 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.