Submissions for variant NM_004168.4(SDHA):c.1423T>C (p.Cys475Arg)

gnomAD frequency: 0.00002  dbSNP: rs781747137

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234575	SCV000288109	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 475 of the SDHA protein (p.Cys475Arg). This variant is present in population databases (rs781747137, gnomAD 0.01%). 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: 239646). 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	RCV000663132	SCV000786271	uncertain significance	Paragangliomas 5	2018-04-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392698	SCV002702704	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-07	criteria provided, single submitter	clinical testing	The c.1423T>C (p.C475R) alteration is located in exon 10 (coding exon 10) of the SDHA gene. This alteration results from a T to C substitution at nucleotide position 1423, causing the cysteine (C) at amino acid position 475 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000663132	SCV004045423	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	RCV003475068	SCV004200634	uncertain significance	Dilated cardiomyopathy 1GG	2023-06-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998527	SCV005624076	uncertain significance	not provided	2024-02-02	criteria provided, single submitter	clinical testing	The SDHA c.1423T>C (p.Cys475Arg) variant has not been reported in individuals with SDHA-related conditions in the published literature. The frequency of this variant in the general population, 0.00012 (4/34592 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.