Submissions for variant NM_001018005.2(TPM1):c.40G>T (p.Asp14Tyr)

dbSNP: rs876661210

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213187	SCV000279798	uncertain significance	not provided	2016-01-19	criteria provided, single submitter	clinical testing	The D14Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D14Y 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. However, no data from this individual's reported ethnic background was available to assess for a population specific benign variant. The D14Y 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 conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, one missense variant in nearby a residue (K15N) has been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014).
Invitae	RCV001854749	SCV002260966	likely pathogenic	Hypertrophic cardiomyopathy	2021-10-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 234774). This missense change has been observed in individual(s) with dilated cardiomyopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 14 of the TPM1 protein (p.Asp14Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.