ClinVar Miner

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

gnomAD frequency: 0.00662  dbSNP: rs113984787
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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: 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.
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 2024-08-01 criteria provided, single submitter clinical testing TRPM4: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics RCV003422113 SCV005209831 likely benign not provided criteria provided, single submitter not provided
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
PreventionGenetics, part of Exact Sciences RCV004530243 SCV004747717 likely benign TRPM4-related disorder 2020-11-02 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).

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