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

gnomAD frequency: 0.00001  dbSNP: rs786203457

Total submissions: 9

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	2023-12-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995530	SCV004836972	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 127 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant, however histidine-127 is a key amino acid for heme binding (PMID: 15989954) and mutations of this residue abolish SDHC protein levels, destabilize of SDHD and SDHB level, and abrogate both succinate ubiquinone oxidoreductase (SQR) and succinate dehydrogenase (SDH) (complex II) enzymatic activities in mitochondria (PMID: 19332149). This variant has been reported in individuals affected with paragangliomas, gastrointestinal stromal tumors (GIST), renal cell carcinoma, and pituitary adenomas (PMID: 23282968, 23666964, 24150194, 24625421, 25025441, 25494863, 29386252, 31308404, 34110302, 34558728). This variant has been identified in 1/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003995530	SCV004847997	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2020-08-10	criteria provided, single submitter	clinical testing	The p.His127Arg variant in SDHC has been reported in 6 individuals with SDHC-related tumors and segregated with disease in 1 affected individual from 1 family (Gill 2013 PMID: 24150194; Miettinen 2013 PMID: 23282968; Denes 2015 PMID: 25494863; Rattenberry 2013 PMID: 23666964; Casey 2019 PMID 31308404; Invitae). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 187084). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant SDHC-related tumors. ACMG/AMP Criteria applied: PM2, PP3, PS4_Strong.
Myriad Genetics, Inc.	RCV004019988	SCV004933699	likely pathogenic	Paragangliomas 3	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25494863, 24150194, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data].
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004019988	SCV005045796	likely pathogenic	Paragangliomas 3	2023-12-12	criteria provided, single submitter	clinical testing