ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.655G>A (p.Asp219Asn)

dbSNP: rs727503518
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000152120 SCV000200806 likely pathogenic Hypertrophic cardiomyopathy 2013-02-14 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Ambry Genetics RCV002362792 SCV002664795 uncertain significance Cardiovascular phenotype 2020-05-13 criteria provided, single submitter clinical testing The p.D219N variant (also known as c.655G>A), located in coding exon 7 of the TPM1 gene, results from a G to A substitution at nucleotide position 655. The aspartic acid at codon 219 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in an individual with hypertrophic cardiomyopathy (HCM), as well as in one individual from an HCM genetic testing cohort; however, clinical details were limited in both cases (Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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.
Invitae RCV000152120 SCV004297614 uncertain significance Hypertrophic cardiomyopathy 2023-04-09 criteria provided, single submitter clinical testing 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 165571). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25524337, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 219 of the TPM1 protein (p.Asp219Asn).

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