Submissions for variant NM_001267550.2(TTN):c.86729AAG[1] (p.Glu28911del)

dbSNP: rs727504797

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156123	SCV000205837	uncertain significance	not specified	2015-07-30	criteria provided, single submitter	clinical testing	The p.Glu26343del variant in TTN has been identified by our laboratory in 1 Cauc asian adult with DCM and has also been identified in 15/66666 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). T his variant is a an in-frame deletion of 1 amino acid at position 26343. It is u nclear if this deletion will impact the protein. In summary, the clinical signif icance of the p.Glu26343 variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000724632	SCV000228568	uncertain significance	not provided	2017-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472404	SCV000543077	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000724632	SCV000730422	likely benign	not provided	2020-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622018	SCV000736942	uncertain significance	Cardiovascular phenotype	2024-08-28	criteria provided, single submitter	clinical testing	The c.59537_59539delAAG variant (also known as p.E19846del) is located in coding exon 153 of the TTN gene. This variant results from an in-frame AAG deletion at nucleotide positions 59537 to 59539. This results in the in-frame deletion of a glutamic acid residue at codon 19846. This variant, designated as p.E26343del, was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear.
New York Genome Center	RCV002467611	SCV002764513	uncertain significance	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2021-12-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724632	SCV003827918	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149952	SCV003837962	uncertain significance	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156123	SCV005039364	uncertain significance	not specified	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: TTN c.79028_79030delAAG (p.Glu26343del) results in an in-frame deletion that is predicted to remove one amino acid from the A-band of the encoded protein. The variant allele was found at a frequency of 0.00017 in 248906 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00017 vs 0.00063), allowing no conclusion about variant significance. c.79028_79030delAAG has been reported in the literature in settings of multigene panel testing in at least two individuals affected with Hypertrophic Cardiomyopathy, without strong evidence for causality (e.g. van Lint_2019, Burstein_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30847666, 32746448). ClinVar contains an entry for this variant (Variation ID: 179334). Based on the evidence outlined above, the variant was classified as uncertain significance.