ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.160G>A (p.Glu54Lys) (rs104894505)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159370 SCV000209316 pathogenic not provided 2016-10-06 criteria provided, single submitter clinical testing The E54K variant in the TPM1 gene has been reported previously in a patient with DCM, and was not reported in 320 control alleles (Olson T et al., 2011). Functional studies show that E54K decreases calcium sensitivity, reduces actin binding, and results in decreased contractility leading to cardiomyopathy pehnotype (Mirza M et al., 2005; Borovikov Y et al., 2009; Memo M et al., 2013). The E54K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the E54K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, pathogenic variants in nearby residues (D58H, E62Q, A63V) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In summary, E54K in the TPM1 gene is interpreted as a pathogenic variant.
Blueprint Genetics RCV000159370 SCV000928000 likely pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing
OMIM RCV000013274 SCV000033521 pathogenic Dilated cardiomyopathy 1Y 2001-04-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (TPM1) RCV000013274 SCV000045876 not provided Dilated cardiomyopathy 1Y 2012-04-15 no assertion provided curation

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