Submissions for variant NM_004168.4(SDHA):c.92G>A (p.Arg31Gln)

gnomAD frequency: 0.00001  dbSNP: rs752532780

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000225880	SCV000288158	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 31 of the SDHA protein (p.Arg31Gln). This variant is present in population databases (rs752532780, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SDHA-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 239687). 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. 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	RCV000410721	SCV000488434	uncertain significance	Paragangliomas 5	2016-03-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571153	SCV000664495	likely benign	Hereditary cancer-predisposing syndrome	2023-02-01	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.
Fulgent Genetics, Fulgent Genetics	RCV002478861	SCV000895695	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-09-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001589187	SCV001823399	uncertain significance	not provided	2021-03-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27683039)
Sema4, Sema4	RCV000571153	SCV002527777	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV001589187	SCV003819244	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410721	SCV004045387	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	RCV003475078	SCV004200580	uncertain significance	Dilated cardiomyopathy 1GG	2024-01-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001589187	SCV004220329	uncertain significance	not provided	2023-02-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00022 (4/18394 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 as a likely germline variant in an individual with acute lymphoblastic leukemia (PMID: 27683039 (2016)). 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.
PreventionGenetics, part of Exact Sciences	RCV004532891	SCV004743336	uncertain significance	SDHA-related disorder	2023-12-31	criteria provided, single submitter	clinical testing	The SDHA c.92G>A variant is predicted to result in the amino acid substitution p.Arg31Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/239687/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.