Submissions for variant NM_001018005.2(TPM1):c.267C>G (p.Asn89Lys)

dbSNP: rs1085307487

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489107	SCV000576560	uncertain significance	not provided	2017-04-27	criteria provided, single submitter	clinical testing	The N89K variant has not been published as pathogenic or been reported as benign to our knowledge. The N89K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N89K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (D84N, V85I, L88M, I92T, V95A) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), and/or reported as likely pathogenic/pathogenic by at least one clinical laboratory.
Invitae	RCV001865507	SCV002183021	uncertain significance	Hypertrophic cardiomyopathy	2022-11-07	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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 426179). This variant has not been reported in the literature in individuals affected with TPM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 89 of the TPM1 protein (p.Asn89Lys).
Ambry Genetics	RCV003302723	SCV004003149	uncertain significance	Cardiovascular phenotype	2023-05-18	criteria provided, single submitter	clinical testing	The p.N89K variant (also known as c.267C>G), located in coding exon 3 of the TPM1 gene, results from a C to G substitution at nucleotide position 267. The asparagine at codon 89 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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.