ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.23C>G (p.Ser8Trp)

gnomAD frequency: 0.00001  dbSNP: rs878854631
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228753 SCV000288133 uncertain significance Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 8 of the SDHA protein (p.Ser8Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 239665). 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.
GeneDx RCV001762532 SCV002008862 uncertain significance not provided 2020-02-04 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002444900 SCV002732557 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-27 criteria provided, single submitter clinical testing The p.S8W variant (also known as c.23C>G), located in coding exon 1 of the SDHA gene, results from a C to G substitution at nucleotide position 23. The serine at codon 8 is replaced by tryptophan, an amino acid with highly dissimilar properties. 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.
Baylor Genetics RCV003475075 SCV004202382 uncertain significance Dilated cardiomyopathy 1GG 2023-10-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001762532 SCV004220299 uncertain significance not provided 2023-07-03 criteria provided, single submitter clinical testing This variant has not been reported in individuals with SDHA-related conditions in the published literature. The frequency of this variant in the general population, 0.000009 (1/111128 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.

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