Submissions for variant NM_001018005.2(TPM1):c.845C>G (p.Thr282Ser)

gnomAD frequency: 0.00003  dbSNP: rs397516395

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094380	SCV000393217	uncertain significance	Hypertrophic cardiomyopathy 3	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000358602	SCV000393218	uncertain significance	Dilated cardiomyopathy 1Y	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000310785	SCV000558814	likely benign	Hypertrophic cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618089	SCV000736917	likely benign	Cardiovascular phenotype	2017-09-19	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	RCV000771818	SCV000904521	likely benign	Cardiomyopathy	2018-10-05	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293082	SCV001434065	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
GeneDx	RCV001578243	SCV001805797	likely benign	not provided	2019-03-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26265630)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036369	SCV000060021	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000036369	SCV000280547	uncertain significance	not specified	2012-12-02	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.Thr282Ser (c.845C>G) in the TPM1 gene was identified. This variant is novel. It has not been reported in association with disease nor as a common polymorphism. This is a conserved amino acid change of a polar Threonine replaced with a polar Serine. Threonine is highly conserved across species at position 282 in the TPM1 gene. A variant in a neighboring codon (Met281Thr) has been reported in association with Hypertrophic Cardiomyopathy (van Driest et al 2003). There are no other reported variants associated with disease in this region. In silico analysis predicts the amino acid change to be benign to protein function (PolyPhen 2). This variant was not observed in 100 presumably healthy control individuals of Caucasian descent at GeneDx. Additionally GeneDx did note the presence of the variant in a patient who was tested for HCM, this individual also carried a disease causing variant in a different sarcomere gene. The variant is not listed in either dbSNP or 1000 genomes (as of July 5th, 2011).