Submissions for variant NM_001018005.2(TPM1):c.797A>G (p.Lys266Arg)

gnomAD frequency: 0.00021  dbSNP: rs371934474

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154863	SCV000204545	uncertain significance	not specified	2014-01-17	criteria provided, single submitter	clinical testing	The Lys266Arg variant in TPM1 has not been previously reported in any other fami lies with cardiomyopathy, but has been identified in 1/4406 African American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an imp act to the protein. Additional information is needed to fully assess the clinica l significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475992	SCV000547689	likely benign	Hypertrophic cardiomyopathy	2023-06-18	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624321	SCV000740437	uncertain significance	Left ventricular noncompaction	2017-07-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154863	SCV000920324	uncertain significance	not specified	2018-11-19	criteria provided, single submitter	clinical testing	Variant summary: TPM1 c.797A>G (p.Lys266Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 277096 control chromosomes, predominantly within the African subpopulation at a frequency of 0.00083 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPM1 causing Cardiomyopathy phenotype (7.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.797A>G has been reported in the literature in two individuals affected with Cardiomyopathy (Walsh 2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507881	SCV001713705	uncertain significance	not provided	2021-03-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798504	SCV002042872	likely benign	Cardiomyopathy	2020-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415660	SCV002678041	likely benign	Cardiovascular phenotype	2023-05-08	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.
Color Diagnostics, LLC DBA Color Health	RCV001798504	SCV004360790	likely benign	Cardiomyopathy	2023-03-08	criteria provided, single submitter	clinical testing