ClinVar Miner

Submissions for variant NM_003001.3(SDHC):c.149G>T (p.Arg50Leu) (rs769177037)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526350 SCV000641425 uncertain significance Gastrointestinal stroma tumor; Paragangliomas 3 2017-03-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 50 of the SDHC protein (p.Arg50Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an SDHC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg50Cys) has been determined to be likely pathogenic (PMID: 23175444, 27279923, 24102379, 19351833, 23666964, Invitae database). This suggests that the arginine residue is critical for SDHC protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and affects an amino acid residue important for protein function, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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