Submissions for variant NM_017636.4(TRPM4):c.1324C>T (p.Arg442Cys)

gnomAD frequency: 0.00010  dbSNP: rs148867331

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067180	SCV001232224	uncertain significance	Progressive familial heart block type IB	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 442 of the TRPM4 protein (p.Arg442Cys). This variant is present in population databases (rs148867331, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TRPM4-related conditions (PMID: 26820365, 30847666). ClinVar contains an entry for this variant (Variation ID: 860804). 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 disruptive. 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	RCV001759840	SCV002006539	uncertain significance	not provided	2022-08-03	criteria provided, single submitter	clinical testing	Reported in one individual with cardiac conduction defect and one individual with unspecified arrhythmia (Daumy et al., 2016; van Lint et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26820365, 30142439, 30847666)
Ambry Genetics	RCV002379602	SCV002690468	uncertain significance	Cardiovascular phenotype	2019-09-18	criteria provided, single submitter	clinical testing	The p.R442C variant (also known as c.1324C>T), located in coding exon 11 of the TRPM4 gene, results from a C to T substitution at nucleotide position 1324. The arginine at codon 442 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in a progressive cardiac conduction disease cohort and was detected in one individual with right bundle branch block and left anterior hemiblock, who also had an SCN5A variant (Daumy X et al. Int. J. Cardiol., 2016 Mar;207:349-58). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002505647	SCV002815748	uncertain significance	Progressive familial heart block type IB; Erythrokeratodermia variabilis et progressiva 6	2022-02-10	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001759840	SCV005196879	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing