ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.647A>G (p.Tyr216Cys) (rs1553177291)

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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 RCV000572107 SCV000664558 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing The p.Y216C variant (also known as c.647A>G), located in coding exon 7 of the SDHB gene, results from an A to G substitution at nucleotide position 647. The tyrosine at codon 216 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in at least one Chinese patient with isolated, malignant head and neck paraganglioma (Chen H et al. J. Cancer Res. Clin. Oncol. 2017 Jun;143:953-960; Zhu WD et al. Eur J Med Genet 2015 Sep;58:433-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000633963 SCV000755236 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 216 of the SDHB protein (p.Tyr216Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with paraganglioma (PMID: 26096992). ClinVar contains an entry for this variant (Variation ID: 480804). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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