Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002432431 | SCV002728027 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-12-16 | criteria provided, single submitter | clinical testing | The p.R72G pathogenic mutation (also known as c.214C>G), located in coding exon 4 of the SDHC gene, results from a C to G substitution at nucleotide position 214. The arginine at codon 72 is replaced by glycine, an amino acid with dissimilar properties. This mutation has been reported in a 32-year-old female individual with a norepinephrine-positive head and neck paraganglioma (Else T et al. J. Clin. Endocrinol. Metab., 2014 Aug;99:E1482-6). Another alteration at the same codon, p.R72H (c.215G>A), has been described in multiple individuals with a paraganglioma (Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27; Buffet A et al. Horm Metab Res, 2012 May;44:359-66; Gupta S et al. Endocr Pathol, 2016 Sep;27:243-52). Based on internal structural analysis, p.R72G disrupts the catalytic function of succinate dehydrogenase, via impacts on quinone binding and/or reduction to quinol (Sun F et al. Cell, 2005 Jul;121:1043-57; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60; Kluckova K et al. Cell Death Dis, 2015 May;6:e1749). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV003098662 | SCV003261008 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 3 | 2023-08-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 72 of the SDHC protein (p.Arg72Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SDHC-related conditions (PMID: 24758179). ClinVar contains an entry for this variant (Variation ID: 1786711). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg72 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17636259, 18212813, 19454582, 24758179, 25950479, 27262318, 27867439; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |