ClinVar Miner

Submissions for variant NM_001018005.1(TPM1):c.475G>A (p.Asp159Asn) (rs397516373)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000679884 SCV000807281 uncertain significance Dilated cardiomyopathy 1Y 2017-09-01 criteria provided, single submitter clinical testing This variant was found once in our laboratory de novo in a 1-year-old female with left ventricular noncompaction, hypotonia, failure to thrive, developmental delay, and microcephaly.
GeneDx RCV000159410 SCV000209356 likely pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing The D159N likely pathogenic variant in the TPM1 gene has been reported previously as an apparently de novo variant in a 2 year-old female with a complex cardiac phenotype of LVNC, Ebstein anomaly with severe tricuspid regurgitation, pulmonary hypertension, and biventricular systolic heart failure (Kelle et al., 2016). D159N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, the D159N variant is not observed in large population cohorts (Lek et al., 2016).
Integrated Genetics/Laboratory Corporation of America RCV000722121 SCV000696597 uncertain significance not specified 2018-05-03 criteria provided, single submitter clinical testing Variant summary: TPM1 c.475G>A (p.Asp159Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.475G>A has been reported in the literature as a de novo variant found in a "2 year-old female with EA, severe tricuspid valve regurgitation, LVNC, pulmonary hypertension, and end-stage heart failure" (Kelle_2016). This data does not allow unequivocal conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as "VUS - possibly pathogenic."
Invitae RCV000694039 SCV000822465 likely pathogenic Hypertrophic cardiomyopathy 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 159 of the TPM1 protein (p.Asp159Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Ebstein anomaly, left ventricular noncompaction cardiomyopathy (LVNC), and end-stage heart failure (PMID: 27177193). In addition, this variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43420). A computational algorithm designed to assess the pathogenicity of variants in TPM1 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036335 SCV000059987 likely pathogenic Primary dilated cardiomyopathy 2011-10-11 criteria provided, single submitter clinical testing
OMIM RCV000736013 SCV000864233 pathogenic Left ventricular noncompaction 9 2019-01-15 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.