Submissions for variant NM_004168.4(SDHA):c.1535G>A (p.Arg512Gln)

dbSNP: rs192818312

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228640	SCV000288116	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-28	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 512 of the SDHA protein (p.Arg512Gln). This variant is present in population databases (rs192818312, gnomAD 0.003%). 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: 239651). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Genetic Services Laboratory, University of Chicago	RCV000502879	SCV000596996	uncertain significance	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399826	SCV002706697	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	The p.R512Q variant (also known as c.1535G>A), located in coding exon 11 of the SDHA gene, results from a G to A substitution at nucleotide position 1535. The arginine at codon 512 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002487068	SCV002792759	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502879	SCV004122158	uncertain significance	not specified	2023-10-03	criteria provided, single submitter	clinical testing	Variant summary: SDHA c.1535G>A (p.Arg512Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250030 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1535G>A in individuals affected with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003475071	SCV004200599	uncertain significance	Dilated cardiomyopathy 1GG	2023-08-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477819	SCV004220279	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with mitochondrial disease-associated epilepsy and cognitive disability (PMID: 36183138 (2022)). The frequency of this variant in the general population, 0.00002 (5/250030 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV003477819	SCV005375628	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge