ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1919A>G (p.Glu640Gly) (rs372480044)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574591 SCV000664530 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000663177 SCV000786344 uncertain significance Paragangliomas 5 2018-04-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765835 SCV000897230 uncertain significance Leigh syndrome; Mitochondrial complex II deficiency; Dilated cardiomyopathy 1GG; Paragangliomas 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000836807 SCV000978653 likely benign not provided 2018-04-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000239361 SCV000297689 uncertain significance Mitochondrial complex II deficiency; Paragangliomas 5 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 640 of the SDHA protein (p.Glu640Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. While this variant is present in population databases (rs372480044), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in a single family in two individuals affected with papillary thyroid cancer and/or gastrointestinal stromal tumors, and in 3 unaffected individuals (PMID: 27493882). ClinVar contains an entry for this variant (Variation ID: 252908). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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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