Submissions for variant NM_001018005.2(TPM1):c.787C>G (p.Gln263Glu)

dbSNP: rs730881147

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159386	SCV000209332	uncertain significance	not provided	2014-06-16	criteria provided, single submitter	clinical testing	The Q263E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q263E 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. The Q263E 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. Nevertheless, in silico analysis predicts this variant likely does not alter the protein structure/function. Missense mutations in nearby residues have not been reported in association with disease, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Center for Human Genetics, University of Leuven	RCV000768534	SCV000886853	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000768534	SCV002199425	uncertain significance	Hypertrophic cardiomyopathy	2021-12-17	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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 181674). This missense change has been observed in individual(s) with clinical features of TPM1-related conditions (PMID: 26688388, 31513939; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 263 of the TPM1 protein (p.Gln263Glu).