Submissions for variant NM_001267550.2(TTN):c.98989+1G>A

dbSNP: rs112240298

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184286	SCV000236909	pathogenic	not provided	2013-05-09	criteria provided, single submitter	clinical testing	Although the c.94066+1 G>A mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 303 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, the c.94066+1 G>A mutation is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, c.94066+1 G>A was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in DCM panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217239	SCV000271287	likely pathogenic	Primary dilated cardiomyopathy	2015-01-26	criteria provided, single submitter	clinical testing	The c.91285+1G>A variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant occurs in the i nvariant region (+/- 1,2) of the splice consensus sequence and is predicted to c ause altered splicing leading to an abnormal or absent protein. Splice and other truncating variants in TTN are strongly associated with DCM, particularly if th ey are located in the exons encoding for the A-band region of the protein (Herma n 2012, Pugh 2014), where this variant is located. In summary, although addition al studies are required to fully establish its clinical significance, the c.9128 5+1G>A variant is likely pathogenic.
Invitae	RCV001225100	SCV001397336	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-22	criteria provided, single submitter	clinical testing	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. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 202428). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 353 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein.
Ambry Genetics	RCV002372129	SCV002662279	likely pathogenic	Cardiovascular phenotype	2022-02-03	criteria provided, single submitter	clinical testing	The c.71794+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 180 of the TTN gene. Exon 180 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%). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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. This alteration has been observed in individuals with a personal and/or family history that is consistent with TTN-related disease (Ambry internal data; Gene Dx pers. comm.; Invitae pers. comm.). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.