ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.377A>G (p.Tyr126Cys) (rs898854295)

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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 RCV000492617 SCV000581216 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence
GeneDx RCV000523379 SCV000619404 likely pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted SDHC c.377A>G at the cDNA level, p.Tyr126Cys (Y126C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in at least one individual with a carotid paraganglioma (Lozano S?nchez 2010). SDHC Tyr126Cys was not observed in large population cohorts (Lek 2016). This variant is located within the helical transmembrane domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider SDHC Tyr126Cys to be a likely pathogenic variant.
Invitae RCV000551177 SCV000641438 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 3 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 126 of the SDHC protein (p.Tyr126Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with paragangliomas (Invitae). ClinVar contains an entry for this variant (Variation ID: 428933). 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"). 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505370 SCV000599554 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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