Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000164275 | SCV000214900 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-17 | criteria provided, single submitter | clinical testing | The p.R230L pathogenic mutation (also known as c.689G>T), located in coding exon 7 of the SDHB gene, results from a G to T substitution at nucleotide position 689. The arginine at codon 230 is replaced by leucine, an amino acid with dissimilar properties. This variant has been described in multiple unrelated individuals with extra-adrenal paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr; 69(8):3650-6; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun; 17(2):94-100; Jasperson KW et al. Fam. Cancer. 2013 Aug; Michaowska I et al. Neuroendocrinology. 2015 ; 101(4):321-30; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). Two other alterations at the same codon, p.R230H (c.689G>A) and p.R230C (c.688C>T), have been detected in numerous individuals diagnosed with pheochromocytomas and/or paragangliomas (Gimenez-Roqueplo AP et al. Cancer Res. 2003 Sep 1;63(17):5615-21; Dahia PL et al. PLoS Genet. 2005 Jul;1(1):72-80; Neumann HP et al. Cancer Res. 2009 Apr 15;69(8):3650-6; Sevilla MA et al. Otolaryngol Head Neck Surg. 2009 May;140(5):724-9; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Cerecer-Gil et al. Clin Cancer Res 2010 Aug 15; 16(16):4148-54; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). 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. |
Labcorp Genetics |
RCV000473831 | SCV000554032 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 230 of the SDHB protein (p.Arg230Leu). This variant is present in population databases (rs587782604, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma (PMID: 18382370, 19351833, 23934599, 27539324). ClinVar contains an entry for this variant (Variation ID: 184933). 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%. This variant disrupts the p.Arg230 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16912137, 20592014, 25405498, 26259135). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000522081 | SCV000616874 | pathogenic | not provided | 2023-06-07 | 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27539324, 25791839, 25371406, 19351833, 23934599, 18382370, 32501622, 30787465, 35668420, 31492822, 32741965, 34906457) |
Institute for Clinical Genetics, |
RCV000522081 | SCV004026073 | pathogenic | not provided | 2022-07-01 | criteria provided, single submitter | clinical testing | PS4, PP3, PM5_STR, PM2_SUP |
Baylor Genetics | RCV003474855 | SCV004203023 | likely pathogenic | Gastrointestinal stromal tumor | 2023-05-02 | criteria provided, single submitter | clinical testing |