Submissions for variant NM_001267550.2(TTN):c.14093-1G>A

gnomAD frequency: 0.00001  dbSNP: rs869312099

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209734	SCV000189749	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Eurofins Ntd Llc (ga)	RCV000296352	SCV000340883	uncertain significance	not provided	2016-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000680134	SCV000807578	pathogenic	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	2017-09-01	criteria provided, single submitter	clinical testing	This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory with a missense variant (I7241V - phase unknown) in a newborn male with hypotonia, minimal movements, arthrogyposis multiplex, mild asymmetry of olfactory bulbs, PFO, femur fractures, family history of a sister with a similar phenotype (not tested)
Invitae	RCV000794667	SCV000934088	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 48 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 223347). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000296352	SCV001789367	uncertain significance	not provided	2019-11-27	criteria provided, single submitter	clinical testing	Reported in a patient from the Jackson Heart Studies cohort who had normal cardiac testing (Roberts et al., 2015); Reported in ClinVar (ClinVar Variant ID# 223347; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in an in-frame deletion of exon 46 in the I-band region; This variant is associated with the following publications: (PMID: 22335739, 23975875, 25326635, 26701604, 25589632)
AiLife Diagnostics, AiLife Diagnostics	RCV000296352	SCV002502875	likely pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381721	SCV002689838	uncertain significance	Cardiovascular phenotype	2023-04-19	criteria provided, single submitter	clinical testing	The c.13004-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 45 of the TTN gene. Coding exon 45 is located in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant has been reported in the Jackson Heart Study cohort with alternate nomenclature (NM_001267550.1: c.14093-1G>A); however, clinical details were limited (Roberts AM et al. Sci Transl Med. 2015 Jan;7(270):270ra6). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003152599	SCV003841206	uncertain significance	Dilated cardiomyopathy 1G		criteria provided, single submitter	clinical testing