Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000036362 | SCV000060014 | uncertain significance | not specified | 2012-10-31 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Ala277Thr varia nt in TPM1 has not been reported in the literature. This variant has been identi fied in 2 Black individuals with HCM tested by our laboratory (including this in dividual) and has been identified in 1/4406 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS; dbSNP rs149659674). Alanine (Ala) at position 277 is not well conserve d in evolution with several species carrying the mutant amino acid (threonine). This suggests that this variant is tolerated but is insufficient to rule out a role in disease. Additional information is needed to fully assess the clinical s ignificance of the Ala277Thr variant. |
Color Diagnostics, |
RCV001192355 | SCV001360403 | uncertain significance | Cardiomyopathy | 2023-09-28 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with threonine at codon 277 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257) and dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 8/282436 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. |
Invitae | RCV001852756 | SCV002156020 | uncertain significance | Hypertrophic cardiomyopathy | 2023-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 277 of the TPM1 protein (p.Ala277Thr). This variant is present in population databases (rs149659674, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 43442). 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 tolerated. 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. |
Fulgent Genetics, |
RCV002496557 | SCV002794517 | uncertain significance | Hypertrophic cardiomyopathy 3; Dilated cardiomyopathy 1Y | 2021-09-03 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003343609 | SCV004074915 | uncertain significance | Cardiovascular phenotype | 2023-08-26 | criteria provided, single submitter | clinical testing | The p.A277T variant (also known as c.829G>A), located in coding exon 9 of the TPM1 gene, results from a G to A substitution at nucleotide position 829. The alanine at codon 277 is replaced by threonine, an amino acid with similar properties. This variant has been reported in hypertrophic and dilated cardiomyopathy cohorts, but clinical details were limited (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Stroeks SLVM et al. Genet Med, 2021 Nov;23:2186-2193). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |