ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1724C>T (p.Ala575Val) (rs750327309)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572994 SCV000674974 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000663257 SCV000786484 uncertain significance Paragangliomas 5 2018-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000487393 SCV000570527 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing The A575V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A575V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A575V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000467983 SCV000553894 uncertain significance Mitochondrial complex II deficiency; Paragangliomas 5 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 575 of the SDHA protein (p.Ala575Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs750327309, ExAC 0.005%). This variant has not been reported in the literature in individuals with SDHA-related disease. ClinVar contains an entry for this variant (Variation ID: 412376). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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