ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 54 of the TPM1 protein (p.Glu54Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 11273725). ClinVar contains an entry for this variant (Variation ID: 12458). 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. Experimental studies have shown that this missense change affects TPM1 function (PMID: 16043485, 17556658, 19222994, 19646950, 23077624, 23539503, 25520664, 27878731). 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.

The p.E54K variant (also known as c.160G>A), located in coding exon 2 of the TPM1 gene, results from a G to A substitution at nucleotide position 160. The glutamic acid at codon 54 is replaced by lysine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with TPM1- related cardiomyopathy and segregated with disease in at least one family (Olson TM et al. J Mol Cell Cardiol, 2001 Apr;33:723-32; Ambry internal data; external communication). In multiple assays testing TPM1 function, this variant showed functionally abnormal results (Mirza M et al. J Biol Chem, 2005 Aug;280:28498-506; Chang AN et al. Front Physiol, 2014 Dec;5:460; Borovikov YS et al. Biochem Biophys Res Commun, 2009 Apr;381:403-6; Memo M et al. Cardiovasc Res, 2013 Jul;99:65-73). An animal model expressing this variant exhibited phenotype(s) consistent with TPM1-related disease (Rajan S et al. Circ Res, 2007 Jul;101:205-14). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.