Submissions for variant NM_001267550.2(TTN):c.54811+1G>A

dbSNP: rs1205836993

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001053576	SCV001217845	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 282 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 849575). 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 A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV001784605	SCV002020330	likely pathogenic	not provided	2019-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436611	SCV002752194	likely pathogenic	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The c.27616+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 109 of the TTN gene. Exon 109 is located in the A-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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration disrupts the canonical splice site and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site variants) in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486959	SCV004239949	likely pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing