ClinVar Miner

Submissions for variant NM_017636.4(TRPM4):c.1783C>G (p.Leu595Val)

gnomAD frequency: 0.00018  dbSNP: rs144812913
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000824083 SCV000964965 uncertain significance Progressive familial heart block type IB 2024-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 595 of the TRPM4 protein (p.Leu595Val). This variant is present in population databases (rs144812913, gnomAD 0.04%). This missense change has been observed in individual(s) with sudden death (PMID: 30391667). ClinVar contains an entry for this variant (Variation ID: 665736). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TRPM4 function (PMID: 30391667). 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.
GeneDx RCV001766756 SCV002008857 uncertain significance not provided 2020-10-19 criteria provided, single submitter clinical testing Observed in a child with sudden cardiac death (SUbbotina et al., 2018); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #665736; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published in vitro functional studies suggest that this variant may impair channel function (Subbotina et al., 2018); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 30391667)
Ambry Genetics RCV002397742 SCV002713468 likely benign Cardiovascular phenotype 2023-12-08 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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