Submissions for variant NM_017636.4(TRPM4):c.2254C>T (p.Gln752Ter)

gnomAD frequency: 0.00041  dbSNP: rs769917929

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414033	SCV000492369	uncertain significance	not specified	2016-12-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TRPM4 gene. The Q752X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Q752X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Nevertheless, only one nonsense variant (W525X) has been reported in HGMD in association with sudden unexpected death in infancy (Stenson et al., 2014), and haploinsufficiency is not a well-established disease mechanism for the TRPM4 gene. Moreover, the Exome Aggregation Consortium reports Q752X was observed in 26/5080 (0.5%) alleles from individuals of European (Non-Finnish) background, indicating it may be a rare benign variant in these populations.
Ambry Genetics	RCV000618995	SCV000736388	likely benign	Cardiovascular phenotype	2018-02-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645473	SCV000767218	benign	Progressive familial heart block type IB	2024-01-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000645473	SCV001292268	uncertain significance	Progressive familial heart block type IB	2019-01-09	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV003422382	SCV004140392	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	TRPM4: BS2
PreventionGenetics, part of Exact Sciences	RCV004544727	SCV004764631	likely benign	TRPM4-related disorder	2022-08-26	no assertion criteria provided	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).