Submissions for variant NM_003000.3(SDHB):c.650G>A (p.Arg217His)

gnomAD frequency: 0.00003  dbSNP: rs747518441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475294	SCV000554038	likely pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 217 of the SDHB protein (p.Arg217His). This variant is present in population databases (rs747518441, gnomAD 0.002%). This missense change has been observed in individual(s) with paraganglioma (PMID: 31492822). ClinVar contains an entry for this variant (Variation ID: 412491). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. This variant disrupts the p.Arg217 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18753105, 19351833, 19454582, 19802898, 23735539, 24659481, 25047027, 26960314). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics	RCV000986260	SCV001135199	likely pathogenic	Paragangliomas 4	2020-08-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365671	SCV002659203	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.R217H variant (also known as c.650G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 650. The arginine at codon 217 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in individuals with paraganglioma or pheochromocytoma (Bayley JP et al. J Med Genet, 2020 02;57:96-103; Ambry internal data). Based on our internal structural analysis, the variant is predicted to disrupt the protein-protein interaction (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). 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 majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV003228936	SCV003925959	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Observed in an individual with a paraganglioma (Bayley et al., 2020); 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; Also known as R189H; This variant is associated with the following publications: (PMID: 17487275, 27882345, 31492822)
All of Us Research Program, National Institutes of Health	RCV004002006	SCV004830023	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with paraganglioma in the literature (PMID: 31492822). Other variants at amino acid position p.Arg217 of SDHB have been classified as pathogenic in ClinVar (Variation IDs: VCV000967921, VCV000419507, VCV000183735) suggesting that variants at this position are disease causing. This variant has been identified in 2/250910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004568130	SCV005056635	likely pathogenic	Gastrointestinal stromal tumor	2024-01-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003228936	SCV005624034	uncertain significance	not provided	2024-09-27	criteria provided, single submitter	clinical testing	The SDHB c.650G>A (p.Arg217His) variant has been reported in the published literature as a somatic variant in renal cell carcinoma (PMID: 27882345 (2016)) and childhood T-cell acute lymphoblastic leukemia (PMID: 7487275 (2007)). This variant has been observed in the germline state in individuals with Paraganglioma intraabdominalis (PMID: 26960314 (2016)) and head and neck paraganglioma (PMID: 31492822 (2020)). Other missense variants at the same amino acid position, c.649C>T (p.Arg217Cys) and c.650G>T (p.Arg217Leu), have been reported in paraganglioma patients and have been described as likely pathogenic in the published literature and/or online databases (PMID 23175444 (2013), 19454582 (2009), 19351833 (2009), 18382370 (2008), 16080530 (2005), and ClinVar https://www.ncbi.nlm.nih.gov/clinvar). The frequency of this variant in the general population, 0.000008 (2/250910 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.