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

dbSNP: rs104894505

Total submissions: 6

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
Invitae	RCV001317675	SCV001508345	uncertain significance	Hypertrophic cardiomyopathy	2020-03-05	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 11273725). ClinVar contains an entry for this variant (Variation ID: 12458). 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. This variant has been reported to affect TPM1 protein function (PMID: 23077624, 19646950, 27878731, 19222994, 17556658, 16043485, 25520664, 23539503). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 54 of the TPM1 protein (p.Glu54Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000159370	SCV005198854	likely pathogenic	not provided	2023-11-01	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