Submissions for variant NM_017636.4(TRPM4):c.1744G>A (p.Gly582Ser)

gnomAD frequency: 0.00043  dbSNP: rs172149856

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208117	SCV000264272	uncertain significance	Brugada syndrome	2015-05-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029158	SCV000290321	likely benign	Progressive familial heart block type IB	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001090742	SCV000521220	likely benign	not provided	2020-03-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21887725, 22750058, 26350513, 23382873, 27884173, 27207958, 28341588, 26820365)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000029158	SCV000745391	uncertain significance	Progressive familial heart block type IB	2017-11-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000990241	SCV001141119	uncertain significance	Progressive familial heart block, type 1A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000029158	SCV001295714	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.
Ambry Genetics	RCV002399335	SCV002711587	benign	Cardiovascular phenotype	2018-12-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001090742	SCV003799326	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing	The p.Gly582Ser variant (rs172149856) has been previously reported in a cardiac conductive block patient who also carried the p.Ala432Thr variant but this variant has not been reported alone (Stallmeyer et al 2012). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.07 percent and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.05 percent. The glycine at position 582 is moderately conserved (considering 15 species, Alamut v2.7.1) and computational analyses of the effects of the p.Gly582Ser variant on protein structure and function predict this variant to be benign (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Because the p.Gly582Ser variant has not been observed without the p.Ala432Thr variant there is not enough evidence to classify this variant with certainty. Pathogenic variants of TRPM4 are inherited in an autosomal dominant manner and are associated with progressive familial heart block, type IB (MIM: 604599).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700278	SCV005203361	likely benign	not specified	2024-07-21	criteria provided, single submitter	clinical testing
OMIM	RCV000029158	SCV000051803	pathogenic	Progressive familial heart block type IB	2012-01-01	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001090742	SCV001800097	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001090742	SCV001920025	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001090742	SCV001958157	uncertain significance	not provided		no assertion criteria provided	clinical testing