Submissions for variant NM_001018005.2(TPM1):c.271C>T (p.Arg91Cys)

dbSNP: rs1266444831

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001121598	SCV001280231	uncertain significance	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, 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	RCV001121599	SCV001280232	uncertain significance	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, 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.
Color Diagnostics, LLC DBA Color Health	RCV001188551	SCV001355624	uncertain significance	Cardiomyopathy	2019-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 91 of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several Japanese individual affected with hypertrophic cardiomyopathy (PMID: 25389285, 26274955). This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001760087	SCV001989797	uncertain significance	not provided	2019-05-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues (I92M, I92T, V95A) have been reported in the Human Gene Mutation Database and at GeneDx in association with cardiomyopathy (Stenson et al., 2014); however additional evidence is needed to definitively determine pathogenicity
Ambry Genetics	RCV003163273	SCV003863830	uncertain significance	Cardiovascular phenotype	2022-12-14	criteria provided, single submitter	clinical testing	The p.R91C variant (also known as c.271C>T), located in coding exon 3 of the TPM1 gene, results from a C to T substitution at nucleotide position 271. The arginine at codon 91 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with hypertrophic cardiomyopathy (HCM) (Tanaka A et al. J Am Heart Assoc, 2014 Nov;3:e001263). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003586268	SCV004282645	uncertain significance	Hypertrophic cardiomyopathy	2023-06-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 888353). This variant has not been reported in the literature in individuals affected with TPM1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 91 of the TPM1 protein (p.Arg91Cys).