ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.379C>T (p.His127Tyr)

dbSNP: rs1485675090
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001036663 SCV001200039 pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2023-04-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His127 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23666964, 24150194, 25494863). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SDHC function (PMID: 19332149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHC protein function. ClinVar contains an entry for this variant (Variation ID: 835716). This missense change has been observed in individuals with clinical features of paraganglioma-pheochromocytoma syndromes (PMID: 22517557, 23162105, 24758179, 26273102, 30050099). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 127 of the SDHC protein (p.His127Tyr).
Ambry Genetics RCV002354978 SCV002622729 pathogenic Hereditary cancer-predisposing syndrome 2021-05-27 criteria provided, single submitter clinical testing The p.H127Y pathogenic mutation (also known as c.379C>T), located in coding exon 5 of the SDHC gene, results from a C to T substitution at nucleotide position 379. The histidine at codon 127 is replaced by tyrosine, an amino acid with similar properties. This mutation has been reported in multiple individuals with a paraganglioma or pheochromocytoma (Buffet A et al. Horm Metab Res, 2012 May;44:359-66; Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6; Gieldon L et al. Cancers (Basel), 2019 Jun;11:; Richter S et al. Genet Med, 2019 03;21:705-717; Smith JD et al. OTO Open Mar;5:2473974X21995453). Two other alterations at the same codon, p.H127D (c.379C>G) and p.H127R (c.380A>G), have been detected in multiple individuals with a paraganglioma, gastrointestinal stromal tumor, or renal carcinoma (Rattenberry E et al. J Clin Endocrinol Metab, 2013 Jul;98:E1248-56; Dénes J et al. J Clin Endocrinol Metab, 2015 Mar;100:E531-41; Gill AJ et al. Pathology, 2013 12;45:689-91; Pczkowska M et al. Eur J Endocrinol, 2017 Feb;176:143-157; Casey RT et al. Sci Rep, 2019 07;9:10244). Based on internal structural analysis, p.H127Y disrupts the SDHC heme-binding site, within which there are other internally pathogenic variants (Sun F et al. Cell, 2005 Jul;121:1043-57; Fufezan C et al. Proteins, 2008 Nov;73:690-704; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60). In an in vitro functional study, this mutation inhibited complex II assembly and abrogated complex II enzymatic activity (Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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.

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