Submissions for variant NM_001018005.2(TPM1):c.46G>C (p.Glu16Gln)

dbSNP: rs727504290

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159395	SCV000209341	likely pathogenic	not provided	2012-11-07	criteria provided, single submitter	clinical testing	The Glu16Gln variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu16Gln results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Glu16Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Met8Arg, Lys15Asn, Ala22Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Glu16Gln was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Glu16Gln is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170561	SCV001333147	likely pathogenic	Cardiomyopathy	2021-06-10	criteria provided, single submitter	clinical testing
Invitae	RCV000154303	SCV001376520	uncertain significance	Hypertrophic cardiomyopathy	2019-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with glutamine at codon 16 of the TPM1 protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 27532257). ClinVar contains an entry for this variant (Variation ID: 177702). 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"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375511	SCV001572361	uncertain significance	not specified	2021-04-15	criteria provided, single submitter	clinical testing	Variant summary: TPM1 c.46G>C (p.Glu16Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248708 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Gomez_2014, Walsh_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154303	SCV000203963	likely pathogenic	Hypertrophic cardiomyopathy	2013-02-08	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory