Submissions for variant NM_001267550.2(TTN):c.25639+2T>C

dbSNP: rs769452066

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002048668	SCV002298473	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 88 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 (rs769452066, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1516031). 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, 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, internal data). 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.
PreventionGenetics, part of Exact Sciences	RCV004538741	SCV004753427	likely pathogenic	TTN-related disorder	2023-12-13	no assertion criteria provided	clinical testing	The TTN c.25639+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is located in the TTN protein I-band region and no other truncating or splice variants in this exon have been previously reported (Human Gene Mutation Database). RNAseq studies from heart tissue indicate this exon is not commonly included in TTN mRNA transcripts (PSI of 8%-37%); however, this analysis in muscle tissue was not performed (Roberts A.M. et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is less likely to be a risk variant for TTN-related cardiac disorders (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). However, many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, the c.25639+2T>C variant is interpreted as likely pathogenic for recessive TTN-related disorders and uncertain for dominant TTN-related disorders.