ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.362T>C (p.Leu121Pro) (rs775925040)

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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 RCV001020760 SCV001182277 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-09 criteria provided, single submitter clinical testing The p.L121P variant (also known as c.362T>C), located in coding exon 4 of the SDHB gene, results from a T to C substitution at nucleotide position 362. The leucine at codon 121 is replaced by proline, an amino acid with similar properties. This alteration was detected in one individual from a cohort of individuals with Cowden syndrome/Cowden-like syndrome who previously tested negative for PTEN pathogenic variants (Ni Y et al. Clin. Cancer Res., 2012 Sep;18:4954-61). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001071144 SCV001236432 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-03-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 121 of the SDHB protein (p.Leu121Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs775925040, ExAC 0.001%). This variant has been observed in an individual affected with Cowden or Cowden-like syndrome (PMID: 22829200). 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 tolerated, 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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