Submissions for variant NM_133378.4(TTN):c.37385_37387delAAG

dbSNP: rs759525338

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000184304	SCV000051171	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000184304	SCV000236929	uncertain significance	not provided	2014-05-15	criteria provided, single submitter	clinical testing	c.40166_40168delAAG: p.Glu13389del (E13389del) in exon 195 of the TTN gene (NM_001256850.1). The c.40166_40168delAAG variant has not been published as a mutation or as a benign polymorphism to our knowledge. c.40166_40168delAAG results in deletion of Glutamic acid at position 13389 and does not cause a shift in reading frame. Only one in-frame deletion/duplication mutation in the TTN gene has been reported in association with tibial muscular dystrophy. Furthermore, c.40166_40168delAAG is not located in the A-band region of TTN, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). 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 CARDIOMYOPATHY panel(s).
Eurofins Ntd Llc (ga)	RCV000184304	SCV000334527	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473301	SCV000542390	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-14	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584801	SCV000692525	uncertain significance	Arrhythmogenic right ventricular dysplasia 1	2017-03-27	criteria provided, single submitter	research	The TTN Glu13389del results in an in-frame deletion of a glutamine (Glu) at position 13389. We have identified this variant in a proband presenting with sudden cardiac death, they were diagnosed with ARVC at post-mortem. The proband has no family history of disease. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency of 0.0002163, which is higher then expected for an inherited heart condition. The clinical consequence of TTN in-frame deletions are currently unknown. Therefore, we classify TTN Glu13389del as a variant of "uncertain significance" though this may be downgraded in future.
Athena Diagnostics	RCV000184304	SCV001146408	uncertain significance	not provided	2019-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375600	SCV001572506	uncertain significance	not specified	2023-04-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.37385_37387delAAG (p.Glu12462del) results in an in-frame deletion that is predicted to remove one amino acid that is located in the I-band region of the encoded protein. The variant allele was found at a frequency of 0.00015 in 243276 control chromosomes, predominantly at a frequency of 0.00034 and 0.00027 within the East Asian and European subpopulations, respectively (gnomAD database). These frequencies are somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (DCM) phenotype (0.00039). However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in the Swedish (allele frequency: 0.00052), suggesting that the variant might be a benign polymorphism. c.37385_37387delAAG has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual within a cohort with Pediatric Dilated Cardiomyopathy (example, Khan_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as uncertain significance (n=8) (LB, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002399688	SCV002711450	likely benign	Cardiovascular phenotype	2020-09-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000184304	SCV003827905	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000184304	SCV001920672	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000184304	SCV001953255	uncertain significance	not provided		no assertion criteria provided	clinical testing