ClinVar Miner

Submissions for variant NM_017636.4(TRPM4):c.3119T>C (p.Ile1040Thr)

dbSNP: rs1369949906
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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 RCV001386316 SCV001586504 pathogenic Progressive familial heart block type IB 2021-03-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1040 of the TRPM4 protein (p.Ile1040Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant progressive symmetric erythrokeratodermia (PMID: 30528822). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 652587). This variant has been reported to affect TRPM4 protein function (PMID: 30528822). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001759549 SCV002005973 uncertain significance not provided 2021-03-01 criteria provided, single submitter clinical testing Hasnt been reported in association with TRPM4-related cardiac conduction disorder; however, has been reported in two Chinese families with progressive symmetric erythrokeratodermia (PSEK) and no cardiac phenotype mentioned (Wang et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a gain-of-function effect, leading to PSEK (Wang et al., 2019); This variant is associated with the following publications: (PMID: 30528822)
OMIM RCV000808167 SCV000948261 pathogenic Erythrokeratodermia variabilis et progressiva 6 2019-08-09 no assertion criteria provided literature only

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