ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.572G>A (p.Cys191Tyr)

dbSNP: rs2077978456
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001253160 SCV001428735 likely pathogenic Renal neoplasm 2020-02-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001387122 SCV001587662 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 191 of the SDHB protein (p.Cys191Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma and pheochromocytoma (PMID: 19261679, 22241717, 25720320, 30050099). ClinVar contains an entry for this variant (Variation ID: 976001). 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. Experimental studies have shown that this missense change affects SDHB function (PMID: 19261679). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV002290664 SCV002581130 likely pathogenic Paragangliomas 4 2022-07-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV003365294 SCV004055049 likely pathogenic Hereditary cancer-predisposing syndrome 2023-06-15 criteria provided, single submitter clinical testing The p.C191Y variant (also known as c.572G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 572. The cysteine at codon 191 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with paragangliomas and/or pheochromocytomas whose tumors showed loss of expression of SDHB on immunohistochemistry (Goffrini P et al. Hum Mol Genet, 2009 May;18:1860-8; Piccini V et al. Endocr Relat Cancer, 2012 Apr;19:149-55; Santi R et al. Anticancer Res, 2017 Feb;37:805-812). In functional studies, this alteration could not rescue loss of SDH2 in complementation studies, had reduced SDH activity and had increased mitochondrial DNA mutability (Goffrini P et al. Hum Mol Genet, 2009 May;18:1860-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV002290664 SCV004175428 likely pathogenic Paragangliomas 4 2023-01-11 criteria provided, single submitter clinical testing

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