ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.275A>T (p.Asp92Val) (rs786205436)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479419 SCV000569592 likely pathogenic not provided 2016-04-14 criteria provided, single submitter clinical testing This variant is denoted SDHD c.275A>T at the cDNA level, p.Asp92Val (D92V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign; however, another variant at the same residue, SDHD Asp92Tyr, is a well described Dutch pathogenic founder variant (van Schothorst 1998, Hensen 2010). SDHD Asp92Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHD Asp92Val occurs at a position that is conserved across species and is located in the transmembrane helical domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider SDHD Asp92Val to be a likely pathogenic variant.
Invitae RCV000539703 SCV000640156 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2017-04-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 92 of the SDHD protein (p.Asp92Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SDHD-related disease. 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. A different missense substitution at this codon (p.Asp92Tyr) is a well-known founder variant in the Dutch population that has been determined to be pathogenic (PMID: 19584903, 21348866). This suggests that the aspartic acid residue is critical for SDHD protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change that affects an important protein residue. However, the current evidence is not sufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000569878 SCV000664532 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient evidence;Well-characterized mutation at same position;Structural Evidence

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