Submissions for variant NM_001267550.2(TTN):c.44481AGA[1] (p.Glu14828del)

dbSNP: rs727505315

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156856	SCV000206577	uncertain significance	not specified	2015-11-13	criteria provided, single submitter	clinical testing	The p.Glu12260del variant in TTN has been identified by our laboratory in 1 Cauc asian individual with DCM. This variant has also been identified in 6/66668 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org). This variant is a deletion of 1 amino acid at position 12260 and is not predicted to alter the protein reading-frame. It is unclear if this deleti on will impact the protein. In summary, the clinical significance of the p.Glu12 260del variant is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000156856	SCV000740473	uncertain significance	not specified	2016-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000643324	SCV000765011	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000184525	SCV000855068	uncertain significance	not provided	2018-06-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156856	SCV001426794	uncertain significance	not specified	2023-10-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.36780_36782delAGA (p.Glu12260del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 7.1e-05 in 240118 control chromosomes. This frequency is not higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (7.1e-05 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.36780_36782delAGA in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; Internal testing). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798525	SCV002042483	uncertain significance	Cardiomyopathy	2019-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408704	SCV002716680	uncertain significance	Cardiovascular phenotype	2024-03-06	criteria provided, single submitter	clinical testing	The c.17289_17291delAGA variant (also known as p.E5763del) is located in coding exon 68 of the TTN gene. This variant results from an in-frame AGA deletion at nucleotide positions 17289 to 17291. This results in the in-frame deletion of a glutamic acid at codon 5763. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002505181	SCV002812098	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-07-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000184525	SCV003827887	uncertain significance	not provided	2023-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000184525	SCV000237175	not provided	not provided	2014-10-24	no assertion provided	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM-CRDM panel(s).
Clinical Genetics, Academic Medical Center	RCV000184525	SCV001923030	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000184525	SCV001927044	uncertain significance	not provided		no assertion criteria provided	clinical testing