Submissions for variant NM_017636.4(TRPM4):c.742C>T (p.Arg248Cys)

gnomAD frequency: 0.00014  dbSNP: rs373749900

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619512	SCV000736288	uncertain significance	Cardiovascular phenotype	2023-11-23	criteria provided, single submitter	clinical testing	The p.R248C variant (also known as c.742C>T), located in coding exon 6 of the TRPM4 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with additional variants in other cardiac-related genes in a case of sudden unexpected death (Bagnall RD et al. Ann. Neurol., 2016 Apr;79:522-34). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001131449	SCV001291070	uncertain significance	Progressive familial heart block type IB	2017-07-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001131449	SCV002393497	likely benign	Progressive familial heart block type IB	2024-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240332	SCV005885767	likely benign	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: TRPM4 c.742C>T (p.Arg248Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 243780 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 44 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRPM4 causing Progressive Familial Heart Block Type 1B phenotype (2.5e-06). c.742C>T has been reported in the literature in an individual affected with sudden unexpected death in epilepsy who also had VUSs in other genes (Bagnall_2016). This report does not provide unequivocal conclusions about association of the variant with Progressive Familial Heart Block Type 1B. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26704558). ClinVar contains an entry for this variant (Variation ID: 518807). Based on the evidence outlined above, the variant was classified as likely benign.