Submissions for variant NM_001018005.2(TPM1):c.453C>A (p.Ala151=)

gnomAD frequency: 0.64628  dbSNP: rs1071646

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036332	SCV000059984	benign	not specified	2008-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000036332	SCV000169032	benign	not specified	2012-09-25	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.
PreventionGenetics, part of Exact Sciences	RCV003891442	SCV000305848	likely benign	TPM1-related disorder	2023-12-07	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).
Ambry Genetics	RCV000248314	SCV000317582	benign	Cardiovascular phenotype	2015-03-11	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	RCV001094282	SCV000393207	benign	Hypertrophic cardiomyopathy 3	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000280647	SCV000393208	benign	Dilated cardiomyopathy 1Y	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000373427	SCV001000164	benign	Hypertrophic cardiomyopathy	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000989342	SCV001139633	benign	Hypertrophic cardiomyopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177325	SCV001341519	benign	Cardiomyopathy	2018-04-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000280647	SCV002098675	benign	Dilated cardiomyopathy 1Y	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001094282	SCV002098676	benign	Hypertrophic cardiomyopathy 3	2021-09-10	criteria provided, single submitter	clinical testing
Cohesion Phenomics	RCV001177325	SCV003803072	benign	Cardiomyopathy	2022-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036332	SCV003929102	benign	not specified	2023-04-10	criteria provided, single submitter	clinical testing	Variant summary: TPM1 c.453C>A alters a conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.67 in 251338 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 9000 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPM1 causing Cardiomyopathy phenotype (7.5e-05), strongly suggesting that the variant is benign. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
All of Us Research Program, National Institutes of Health	RCV000373427	SCV004815449	benign	Hypertrophic cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (TPM1)	RCV000024584	SCV000045893	not provided	not provided	2012-04-15	no assertion provided	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000036332	SCV001742698	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036332	SCV001917009	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036332	SCV001927465	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036332	SCV001953367	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036332	SCV001976124	benign	not specified		no assertion criteria provided	clinical testing