ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.575G>A (p.Cys192Tyr) (rs397516835)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130852 SCV000185750 pathogenic Hereditary cancer-predisposing syndrome 2019-12-11 criteria provided, single submitter clinical testing The p.C192Y pathogenic mutation (also known as c.575G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 575. The cysteine at codon 192 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple individuals diagnosed with paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435). The cysteine at codon 192 has been shown to play a vital role coordinating the iron-sulfur cluster in SDHB protein (Iverson TM et al. J Biol Chem. 2012 Oct 12;287(42):35430-8). In addition, another alteration at codon 192 (p.C192R) has been reported in two individuals, one with a sporadic pheochromocytoma and the other with a paraganglioma (Neumann HP et al. N Engl J Med. 2002 May 9;3466(19):1459-66; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27). Based on protein sequence alignment, this amino acid position is completely conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505338 SCV000599519 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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