Submissions for variant NM_017636.4(TRPM4):c.2740A>T (p.Lys914Ter)

gnomAD frequency: 0.00094  dbSNP: rs140799936

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084074	SCV000290322	likely benign	Progressive familial heart block type IB	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000387261	SCV000414306	uncertain significance	TRPM4-related disorder	2016-06-14	criteria provided, single submitter	clinical testing	The c.2740A>T (p.Lys914Ter) variant is a stop gained variant that has been reported in at least two studies in which it is found in a heterozygous state in a total of four patients with Brugada syndrome (Liu et al. 2012; Hertz et al. 2015). The p.Lys914Ter variant was reported in two of 1914 controls (Liu et al. 2012) and is reported at a frequency of 0.00221 in the European (Non-Finnish) population of the Exome Aggregation Consortium. There is limited evidence linking the TRPM4 gene to Brugada syndrome. Functional analysis of the p.Lys914Ter variant protein in HEK-293 cells demonstrated the variant resulted in decreased total expression, a truncated protein and a lack of current in a single channel conductance test (Liu et al. 2012). Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Lys914Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for TRPM4-related disorders.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000419640	SCV000510701	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000419640	SCV000514972	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	Reported in both patients with Brugada syndrome and control subjects as well as in a cohort of stillbirth cases (PMID: 23382873, 25467552, 27711072, 30847666, 30615648); Published functional studies demonstrated p.(K914*) resulted in decreased expression of the TRPM4 channel, though a dominant effect was not established because the combined expression of wild-type and mutant TRPM4 channels was not studied (PMID: 23382873); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 30142439, no PMID, 24721656, 22750058, 27711072, 23382873, 30821013, 31345219, 30847666, 36982932, 37128952, 25467552, 30615648)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000419640	SCV000884740	likely benign	not provided	2020-04-03	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852765	SCV000995483	likely benign	Cardiomyopathy	2019-01-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436037	SCV002749401	likely benign	Cardiovascular phenotype	2019-01-24	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.
CeGaT Center for Human Genetics Tuebingen	RCV000419640	SCV004140393	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TRPM4: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV000387261	SCV004744306	likely benign	TRPM4-related disorder	2024-02-05	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).