ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.118G>T (p.Glu40Ter) (rs104894501)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036315 SCV000059967 uncertain significance not specified 2012-06-18 criteria provided, single submitter clinical testing The Glu40X variant in TPM1 has not been reported in the literature nor previousl y identified by our laboratory. This nonsense variant leads to a premature termi nation codon at position 40, which is predicted to lead to a truncated or absent protein. However, heterozygous loss of function of the TPM1 gene is not an esta blished disease mechanism in DCM. In addition, mouse models with loss of a singl e TPM1 allele did not show any morphological or functional differences from wild type mice (Blanchard 1997), though it is not clear if the same impact would be observed in human hearts. In summary, additional studies are needed to fully ass ess the clinical significance of Glu40X variant.
GeneDx RCV000766947 SCV000209315 uncertain significance not provided 2013-09-27 criteria provided, single submitter clinical testing The Glu40Stop variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu40Stop was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Glu40Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, the majority of definitive mutations reported in the TPM1 gene have been missense changes, and haploinsufficiency of tropomysin alpha-1 is not an established mechanism for DCM. The Glu40Stop variant has been identified multiple times at GeneDx, and was subsequently identified in one relative with mild left ventricular dilation as well as in multiple relatives reported to be clinically unaffected. With the clinical and molecular information available at this time, we cannot definitively determine if Glu40Stop is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Ambry Genetics RCV000621859 SCV000737383 uncertain significance Cardiovascular phenotype 2019-03-07 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000700155 SCV000828900 uncertain significance Hypertrophic cardiomyopathy 2018-02-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu40*) in the TPM1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43403). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TPM1 cause disease. 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.
Color RCV001179079 SCV001343668 uncertain significance Cardiomyopathy 2020-05-12 criteria provided, single submitter clinical testing

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