Submissions for variant NM_004168.4(SDHA):c.1273G>A (p.Val425Met)

dbSNP: rs201822097

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231334	SCV000288105	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-27	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 425 of the SDHA protein (p.Val425Met). This variant is present in population databases (rs201822097, gnomAD 0.01%). This missense change has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 23666964). ClinVar contains an entry for this variant (Variation ID: 239642). 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 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.
Ambry Genetics	RCV000569607	SCV000664715	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	The p.V425M variant (also known as c.1273G>A), located in coding exon 10 of the SDHA gene, results from a G to A substitution at nucleotide position 1273. The valine at codon 425 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in two individuals with paraganglioma and/or pheochromocytoma (Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98(7):E1248-56; Casey RT et al. Mol Genet Genomic Med 2017 May;5(3):237-250). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000663187	SCV000786358	uncertain significance	Paragangliomas 5	2018-04-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001753700	SCV002005164	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28500238, 23666964, 31721781, 28546994)
Fulgent Genetics, Fulgent Genetics	RCV002503907	SCV002814451	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-10-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663187	SCV004018617	uncertain significance	Paragangliomas 5	2023-04-21	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	RCV003475066	SCV004200566	uncertain significance	Dilated cardiomyopathy 1GG	2024-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753700	SCV004220264	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with pheochromocytomas and paragangliomas (PMID: 23666964 (2013), 28546994 (2017)). The frequency of this variant in the general population, 0.00012 (4/34592 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.