ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.400T>G (p.Leu134Val) (rs200851392)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573265 SCV000675120 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034698 SCV000043499 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Invitae RCV000464082 SCV000554068 uncertain significance Paraganglioma and gastric stromal sarcoma; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 134 of the SDHD protein (p.Leu134Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs200851392, ExAC 0.003%). This variant has not been reported in the literature in individuals with SDHD-related disease. ClinVar contains an entry for this variant (Variation ID: 41777). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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