Submissions for variant NM_017636.4(TRPM4):c.1459_1494del (p.Lys487_Leu498del)

dbSNP: rs878855029

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001001639	SCV000290318	benign	Progressive familial heart block type IB	2024-01-31	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000496011	SCV000584178	uncertain significance	Brugada syndrome	2016-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620470	SCV000735058	benign	Cardiovascular phenotype	2016-06-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852760	SCV000995478	likely benign	Cardiomyopathy	2017-09-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001706269	SCV001159146	benign	not provided	2023-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001706269	SCV001811694	likely benign	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330601	SCV004038775	benign	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: TRPM4 c.1459_1494del36 (p.Lys487_Leu498del) results in an in-frame deletion that is predicted to remove twelve amino acids from the encoded protein. The variant allele was found at a frequency of 0.0078 in 247918 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4399.99 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1459_1494del36 has been reported in the literature as a polymorphism, and in a patient with a pathogenic variant explaining their phenotype (Syam_2016, Neubauer_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27207958, 33895855). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: five classified the variant as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003977682	SCV004791791	benign	TRPM4-related condition	2020-02-17	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).