Submissions for variant NM_017636.4(TRPM4):c.301G>A (p.Ala101Thr)

gnomAD frequency: 0.00662  dbSNP: rs113984787

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206109	SCV000261955	benign	Progressive familial heart block type IB	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000440103	SCV000521400	benign	not specified	2016-09-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000619013	SCV000735094	benign	Cardiovascular phenotype	2015-12-15	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.
Illumina Laboratory Services, Illumina	RCV000206109	SCV001295587	likely benign	Progressive familial heart block type IB	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440103	SCV004121924	benign	not specified	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: TRPM4 c.301G>A (p.Ala101Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 241570 control chromosomes. The observed variant frequency is approximately 33 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 benign. To our knowledge, no occurrence of c.301G>A in individuals affected with Progressive Familial Heart Block Type 1B and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV003422113	SCV004142170	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	TRPM4: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003937789	SCV004747717	likely benign	TRPM4-related condition	2020-11-02	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).
Clinical Genetics, Academic Medical Center	RCV000440103	SCV001922637	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000440103	SCV001958677	benign	not specified		no assertion criteria provided	clinical testing