Submissions for variant NM_003001.5(SDHC):c.380A>G (p.His127Arg)

gnomAD frequency: 0.00001  dbSNP: rs786203457

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166772	SCV000217585	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	clinical testing	The p.H127R pathogenic mutation (also known as c.380A>G), located in coding exon 5 of the SDHC gene, results from an A to G substitution at nucleotide position 380. The histidine at codon 127 is replaced by arginine, an amino acid with highly similar properties. The mutation has been detected in multiple individuals with paraganglioma(s) (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; Andrews KA et al. J Med Genet, 2018 06;55:384-394; Ambry internal data). It has also been identified in patients with a succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor and/or renal carcinoma (Gill AJ et al. Pathology, 2013 12;45:689-91; Gill AJ et al. Am J Surg Pathol, 2014 Dec;38:1588-602; Casey RT et al. Sci Rep, 2019 07;9:10244; Ambry internal data). Based on internal structural analysis, this mutation 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). 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.
GeneDx	RCV000478217	SCV000565547	likely pathogenic	not provided	2022-12-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23162105, 29386252, 25025441, 31579262, 19332149, 23666964, 26259135, 25494863, 23282968, 25394176, 24886695, 26273102, 23833252, 24625421, 24096523, 27011036, 33087929, 34703596, 34558728, 33237286, 24150194, 34308366, 34110302, 34301805)
Invitae	RCV000641906	SCV000763556	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 3	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 127 of the SDHC protein (p.His127Arg). This variant is present in population databases (rs786203457, gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumor, renal carcinoma and papillary thyroid carcinoma and paraganglioma (PMID: 23666964, 24150194, 25494863; Invitae). ClinVar contains an entry for this variant (Variation ID: 187084). 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 with a positive predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.His127 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been observed in individuals with SDHC-related conditions (PMID: 22517557, 24758179), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523820	SCV001478182	likely pathogenic	Gastrointestinal stromal tumor	2020-12-15	criteria provided, single submitter	research
Baylor Genetics	RCV001523820	SCV004203056	pathogenic	Gastrointestinal stromal tumor	2023-10-06	criteria provided, single submitter	clinical testing