ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.758G>A (p.Cys253Tyr) (rs786201085)

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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 RCV000162580 SCV000212996 likely pathogenic Hereditary cancer-predisposing syndrome 2012-10-03 criteria provided, single submitter clinical testing The p.C253Y variant (also known as c.758G>A) is located in coding exon 7 of the SDHB gene. This alteration results from a G to A substitution at nucleotide position 758. The cysteine at codon 253 is replaced by tyrosine, an amino acid with highly dissimilar properties. Multiple studies have identified this alteration in patients with pheochromocytomas and/or paragangliomas, often with apparently sporadic presentation (Amar L et al. J. Clin Oncol 2005 Dec 1;23(34):8812-8, Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct; 92(10):3822-8, Favier J et al. PLoS ONE 2009;4(9):e7094, Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Pat&oacute;cs A et al. Pathol. Oncol. Res. 2016 Oct;22(4):673-9). Based on protein sequence alignment, this amino acid position is highly conserved and located in a highly conserved region of the protein. <span style="background-color:initial">The Cys253 residue plays a vital role coordinating the Fe4S4 cluster, and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct; 287(42):35430-8).<span style="background-color:initial"> In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico<span style="background-color:initial"> analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001040032 SCV001203587 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-02-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 253 of the SDHB protein (p.Cys253Tyr). 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 observed in individuals affected with paraganglioma-pheochromocytoma syndrome (PMID: 17652212, 19454582, 19763184, 26960314). ClinVar contains an entry for this variant (Variation ID: 183795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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