ClinVar Miner

Submissions for variant NM_003001.3(SDHC):c.380A>G (p.His127Arg) (rs786203457)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166772 SCV000217585 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000478217 SCV000565547 likely pathogenic not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted SDHC c.380A>G at the cDNA level, p.His127Arg (H127R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant was reported in two brothers with head and neck paraganagliomas, one of whom also had a pituitary macroadenoma (D?nes 2015). It was also observed in a patient with papillary thyroid cancer, renal cell cancer, and GIST; both the renal tumor and GIST demonstrated absence of SDHB by IHC (Gill 2013). Andrews et al. (2018) reported this variant in 7 apparently unrelated individuals with a personal or family history of paraganglioma/pheochromocytoma. SDHC His127Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located at the metal binding site for iron and within the helical transmembrane topological domain (UniProt, Lemarie 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider SDHC His127Arg to be a likely pathogenic variant.
Invitae RCV000641906 SCV000763556 uncertain significance Gastrointestinal stroma tumor; Paragangliomas 3 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 127 of the SDHC protein (p.His127Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with paraganglioma (PMID: 25494863, 23666964) and in an individual affected with gastrointestinal stromal tumor, renal carcinoma and papillary thyroid carcinoma (PMID: 24150194). ClinVar contains an entry for this variant (Variation ID: 187084). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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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