Submissions for variant NM_001018005.2(TPM1):c.256G>A (p.Ala86Thr)

dbSNP: rs2034911718

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Goettingen	RCV001281081	SCV001451437	likely pathogenic	Dilated cardiomyopathy 1Y	2020-12-21	criteria provided, single submitter	clinical testing	The variant c.256G>A (p.(Ala86Thr)) in exon 3 of the TPM1-gene is not found in known databases (ExAC or gnomAD) and it has been published in the literature as a variant of unknown significance (PMID: 26688388). Another nucleotide change resulting in another amino acid change at the same position was described as pathogenic (c.257C>T, p.(Ala86Val); PMID: 31568572). The variant affects a highly conserved nucleotide, a highly conserved amino acid, there is a small physicochemical difference between Ala and Thr and the variant is located within a protein domain (Tropomyosin). This variant has a pathogenic computational verdict based on in silico prediction programs. Missense variants in TPM1 are a known mechanism of disease. Thus, we consider this TPM1-variant a likely pathogenic variant. ACMG criteria used for classification: PM1, PM2, PM5, PP2, PP3.
GeneDx	RCV001773588	SCV001992908	uncertain significance	not provided	2021-04-07	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 26688388)
Ambry Genetics	RCV004686650	SCV005178974	uncertain significance	Cardiovascular phenotype	2024-03-24	criteria provided, single submitter	clinical testing	The p.A86T variant (also known as c.256G>A), located in coding exon 3 of the TPM1 gene, results from a G to A substitution at nucleotide position 256. The alanine at codon 86 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual from a dilated cardiomyopathy cohort who also had an additional variant in another cardiac-related gene; however, clinical details were limited (Chanavat V et al. Clin Chim Acta, 2016 Jan;453:80-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.