ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.379A>C (p.Ile127Leu) (rs201372280)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457681 SCV000554007 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 127 of the SDHB protein (p.Ile127Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with early onset renal cell carcinoma (PMID: 23083876). ClinVar contains an entry for this variant (Variation ID: 412472). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). This variant disrupts the p.Ile127 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: 16916404, 19001511, 16317055, 16912137, 17200167, 25683602, 25972245, 29386252, 29951630), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Ambry Genetics RCV000570298 SCV000675062 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-27 criteria provided, single submitter clinical testing The p.I127L variant (also known as c.379A>C), located in coding exon 4 of the SDHB gene, results from an A to C substitution at nucleotide position 379. The isoleucine at codon 127 is replaced by leucine, an amino acid with highly similar properties. In one study, this variant was detected in an individual with kidney cancer at 28 years of age; however, it was also detected in the proband's unaffected mother and two unaffected maternal aunts (Ricketts CJ et al. J. Urol. 2012 Dec;188:2063-71). 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.

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