Submissions for variant NM_001018008.2(TPM1):c.695G>A (p.Arg232His)

gnomAD frequency: 0.00006  dbSNP: rs730881128

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159352	SCV000209298	uncertain significance	not specified	2015-07-28	criteria provided, single submitter	clinical testing	The Arg232His variant in the TPM1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Arg232His occurs in an alternative transcript of TPM1, variant 6 (TMBr-3 brain isoform), which is reported to expressed in brain tissue in animal models (Lees-Miller et al., 1990; Stamm S et al., 1993). No mutations have been reported in this alternative transcript and it is unknown if this gene isoform is also expressed in the heart. Arg232His results in a conservative substitution of one positively charged amino acid for another at a residue that is not conserved across species. As a result, in silico analysis predicts Arg232His likely has a benign effect onthe protein structure/function. However, the NHLBI ESP Exome Variant Server reports Arg232His was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if the Arg232His variant in the TPM1 is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000159352	SCV000270932	likely benign	not specified	2015-02-26	criteria provided, single submitter	clinical testing	p.Arg232His in exon 10A of TPM1: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (38/11578) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org).
Color Diagnostics, LLC DBA Color Health	RCV001190440	SCV001357933	likely benign	Cardiomyopathy	2018-12-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736613	SCV004564087	likely benign	not provided	2023-09-28	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159352	SCV000280542	uncertain significance	not specified	2013-03-05	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg232His (R232H; c.695 G>A) in the TPM1 gene This is a completely novel variant. The testing lab reports that Arg232His occurs in an alternative transcript of TPM1 (TMBr-3 brain isoform), which is expressed in brain tissue in animal models (Lees-Miller et al. 1990, Stamm et al. 1993). No disease-causing mutations have been reported in this alternative transcript (Stenson et al. 2009, the Human Gene Mutation Database) and it is unknown if this gene isoform is also expressed in the heart. This is a conservative amino acid change, resulting in the replacement of a basic, positively-charged arginine with a basic, positively-charged histidine. GeneDx reports that the arginine at this location is not conserved across species and that in silico analysis predicts the change to be benign. This is not a common polymorphism. In total the variant has not been seen in >6500 individuals from publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however, as our patient is of Mexican ancestry. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of December 2, 2012). No variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). It is not found in 1000 genomes (http://browser.1000genomes.org/index.htm), which contained 70 individuals of Mexican ancestry from Los Angeles, as of May 13, 2012.