Submissions for variant NM_003000.3(SDHB):c.649C>T (p.Arg217Cys)

gnomAD frequency: 0.00001  dbSNP: rs200245469

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162444	SCV000212794	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	The p.R217C pathogenic mutation(also known as c.649C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 649. The arginine at codon 217 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in the germline and/or tumor of numerous individuals with paragangliomas (PGL) (Klein RD et al. Diagn Mol Pathol. 2008;17(2):94-100; Burnichon N et al. J Clin Endocrinol Metab. 2009;94(8):2817-27; Pasini B et al. J. Intern. Med. 2009 Jul; 266(1):19-42; Kimura N et al. Endocr. Relat. Cancer 2014 Jun; 21(3):L13-6; Patócs A et al. Pathol. Oncol. Res. 2016 Oct;22(4):673-9; Niemeijer ND et al. Eur. J. Endocrinol., 2017 Aug;177:115-125; Andrews KA et al. J. Med. Genet., 2018 06;55:384-394; Rijken JA et al. BJS Open, 2018 Apr;2:62-69; Richter S et al. Genet. Med., 2019 03;21:705-717; Ambry Internal Data). In one study of nearly 600 patients with head and neck PGL, p.R217C was detected in two individuals, and a second alteration at the same codon, p.R217L, was detected in another individual (Neumann HP et al. Cancer Res. 2009 Apr; 69(8):3650-6). 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.
Invitae	RCV000539362	SCV000644763	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 217 of the SDHB protein (p.Arg217Cys). This variant is present in population databases (rs200245469, gnomAD 0.06%). This missense change has been observed in individuals with paraganglioma-pheochromocytoma syndromes (PMID: 18753105, 19351833, 19454582, 19802898, 23735539, 24659481, 25047027, 26960314). ClinVar contains an entry for this variant (Variation ID: 183735). 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 SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000984327	SCV001132525	likely pathogenic	Paragangliomas 4	2017-12-13	criteria provided, single submitter	curation
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001528474	SCV002010043	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001528474	SCV002028838	likely pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26960314, 23735539, 28503760, 19454582, 17487275, 19802898, 25047027, 27573198, 24659481, 19522823, 16080530, 18382370, 18753105, 21561462, 19351833, 22517557, 29386252, 28490599, 29951630, 34439371, 30201732, 34439168, 32741965, 31212687, 31492822, 33748650, 30050099, 34906457)
CeGaT Center for Human Genetics Tuebingen	RCV001528474	SCV002062406	likely pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466456	SCV002761946	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2022-04-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474840	SCV004203036	likely pathogenic	Gastrointestinal stromal tumor	2022-08-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000984327	SCV004362269	likely pathogenic	Paragangliomas 4	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 217 of the SDHB 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). Functional analysis on an immortalized cell line from a variant carrier showed reduced SDHB protein expression by western blot, inhibition of proliferation and altered metabolite profiles in metformin-treated cells (PMID: 34118692). This variant has been reported in more than 10 individuals and families affected with paraganglioma and/or pheochromocytoma (PMID: 18382370, 18753105, 19454582, 19351833, 19802898, 21561462, 24659481, 23735539, 26960314, 27573198, 29386252, 29951630, 30050099, 30201732, 31212687, 31216007, 32462735, 33748650, 34118692, 34439371, 34439168). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV002466456	SCV004824193	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-04-27	criteria provided, single submitter	clinical testing	The c.649C>T (p.Arg217Cys) variant in the SDHB gene is located on the exon 7 and is predicted to replace arginine with cysteine at codon 217 (p.Arg217Cys). The variant has been reported in more than 10 unrelated individuals affected with paragangliomas (PMID: 33748650, 34439371, 30658386, 16080530, 24659481, 31212687, 29386252, 29951630). Experimental study from the paraganglioma patient cells indicates that this variant promotes tumorigenesis (PMID: 34118692). The variant is reported in ClinVar as pathogenic or likely pathogenic by multiple submitters (ID: 183735). The variant is absent in the general population according to the gnomAD database. Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.988). Therefore, the c.649C>T (p.Arg217Cys) variant of SDHB has been classified as likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528474	SCV001740280	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528474	SCV001957564	pathogenic	not provided		no assertion criteria provided	clinical testing