ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.587G>A (p.Cys196Tyr) (rs876658367)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220162 SCV000273488 pathogenic Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing The p.C196Y pathogenic mutation (also known as c.587G>A or c.721G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 587. The cysteine at codon 196 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation is in the 4Fe-4S ferredoxin-type domain and has been reported in numerous patients with a pheochromocytoma and/or paraganglioma (Neumann HP et al. N. Engl. J. Med. 2002 May; 346(19):1459-66; Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar; 91(3):827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov; 91(11):4505-9; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct; 92(10):3822-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Renella R et al. Fam. Cancer. 2014 Sep;13(3):507-11; Tufton N et al. Endocr. Pathol. 2017 Dec;28(4):320-325). A functional study investigating SDHB missense mutations demonstrated that this variant was associated with accelerated protein degradation and consequent functional insufficiency of the protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001034642 SCV000554025 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 196 of the SDHB protein (p.Cys196Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple unrelated individuals affected with pheochromocytomas (PCC) and/or paragangliomas (PGL), many of whom had malignant tumors or family members affected with PCC or PGL (PMID: 24781345, 21172883, 17652212, 19064958, 23666964, 25683602). ClinVar contains an entry for this variant (Variation ID: 12109652). Experimental studies have shown that this variant causes a higher rate of protein ubiquitination and subsequent faster degradation compared to wild type (PMID: 22835832). In addition, a different missense change at the same codon (p.Cys196Trp) showed severely impaired protein function similar to null alleles in a yeast complementation assay (PMID: 23175444), suggesting that this amino acid residue is important for normal SDHB protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000479413 SCV000568587 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.587G>A at the cDNA level, p.Cys196Tyr (C196Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has been observed in several individuals and families with both malignant and non-malignant paragangliomas/pheochromocytomas, with at least one tumor showing loss of SDHB protein expression via immunohistochemistry (Neumann 2002, Brouwers 2006, Timmers 2008, Burnichon 2009, Hahn 2009, Dubb 2014, Renella 2014, Michalowska 2015, Jochmanova 2017). Cells transfected with SDHB Cys196Tyr demonstrated SDHB protein loss due to a reduced half-life of the variant protein (Yang 2012). SDHB Cys196Tyr was not observed in large population cohorts (Lek 2016). SDHB Cys196Tyr is located in the 4Fe-4S ferredoxin-type domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000461924 SCV000782277 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505388 SCV000599517 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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