Submissions for variant NM_001018005.2(TPM1):c.98A>C (p.Glu33Ala)

dbSNP: rs886039444

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255536	SCV000321978	uncertain significance	not provided	2021-03-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 265279; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543459	SCV000623817	uncertain significance	Hypertrophic cardiomyopathy	2017-04-13	criteria provided, single submitter	clinical testing	This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 265279). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 33 of the TPM1 protein (p.Glu33Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine.
Molecular Genetics, Royal Melbourne Hospital	RCV003993911	SCV004812638	uncertain significance	Primary dilated cardiomyopathy	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in TPM1 is predicted to replace glutamic acid with alanine at codon 33, p.(Glu33Ala). The glutamic acid residue is highly conserved (94/94 vertebrates, UCSC), and is located in the coiled-coiled domain. There is a large physicochemical difference between glutamic acid and alanine. TPM1, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1 missense constraint score = 0.37). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been detected in at least two probands with a phenotype consistent with TPM1-related cardiac conditions (Royal Melbourne Hospital; Invitae). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.703). Another missense variant c.97G>A, p.(Glu33Lys) in the same codon has been reported in individuals with dilated cardiomyopathy (PMID: 24503780, 30847666, 30923642). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS4_Supporting, PM2_Supporting, PP2, PP3.