Submissions for variant NM_017636.4(TRPM4):c.2531G>A (p.Gly844Asp)

gnomAD frequency: 0.00064  dbSNP: rs200038418

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000249699	SCV000320605	uncertain significance	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	The p.G844D variant (also known as c.2531G>A), located in coding exon 17 of the TRPM4 gene, results from a G to A substitution at nucleotide position 2531. The glycine at codon 844 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in conjunction with cardiac conduction defects and arrhythmia in a variety of individuals and has been shown to segregate with disease in one family, but it has also been reported in healthy individuals (Liu H et al. Circ Cardiovasc Genet. 2010;3(4):374-85; Stallmeyer B et al. Hum Mutat. 2012; 33(1):109-17; Liu H et al. PLoS ONE 2013; 8(1):e54131; Celestino-Soper PB et al. PLoS ONE. 2015;10(12):e0143588; Daumy X et al. Int J Cardiol. 2016;207:349-58; Syam N et al. J Am Heart Assoc. 2016;5:e001625; Hof T et al. BMC Med. Genet., 2017 03;18:31; Auricchio A et al. Europace. 2023 Feb;25(2):643-650). Functional studies suggest the potential for gain of function effects (Liu H et al. Circ Cardiovasc Genet. 2010 Aug;3(4):374-85). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000434894	SCV000511321	uncertain significance	not provided	2017-02-14	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Invitae	RCV000029161	SCV000560581	likely benign	Progressive familial heart block type IB	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000434894	SCV000566303	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24721656, 25441424, 25231975, 23382873, 26636822, 21887725, 22750058, 27207958, 27181684, 33381229, 30142439, 21173080, 28494446, 30847666, 35205305, 26820365, 36352534, 28315637, 20562447)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000434894	SCV000605446	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000029161	SCV001295802	uncertain significance	Progressive familial heart block type IB	2017-04-27	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.
PreventionGenetics, part of Exact Sciences	RCV004541017	SCV004779662	likely benign	TRPM4-related disorder	2022-12-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526600	SCV005039793	likely benign	not specified	2024-03-30	criteria provided, single submitter	clinical testing
OMIM	RCV000029161	SCV000051806	pathogenic	Progressive familial heart block type IB	2012-01-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000434894	SCV001922526	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000434894	SCV001974661	uncertain significance	not provided		no assertion criteria provided	clinical testing