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

dbSNP: rs1205836993

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001053576	SCV001217845	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-09-17	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 (PMID: 33996946; internal data). 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	2023-05-15	criteria provided, single submitter	clinical testing	The c.27616+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 110 (coding exon 109) of the TTN gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Exon 110 (coding 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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, 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
GeneDx	RCV001784605	SCV005391461	likely pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33996946, 22335739)