Submissions for variant NM_001267550.2(TTN):c.64673-2A>G

dbSNP: rs2154180194

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002012601	SCV002278052	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-06-01	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). This sequence change affects an acceptor splice site in intron 309 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). 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: 1493270). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Ambry Genetics	RCV004045405	SCV005020541	uncertain significance	Cardiovascular phenotype	2023-12-22	criteria provided, single submitter	clinical testing	The c.37478-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 137 in the TTN gene. Coding exon 137 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 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.
GeneDx	RCV005254004	SCV005906867	likely pathogenic	not provided	2024-10-02	criteria provided, single submitter	clinical testing	Reported in an individual with DCM in published literature who harbored additional cardiogenetic variants (PMID: 39135814); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Located in the A-band, a region of TTN for which truncating variants are significantly associated with autosomal dominant cardiomyopathy and also with autosomal recessive skeletal myopathies (PMID: 22335739, 32778822); This variant is associated with the following publications: (PMID: 39135814, 22335739, 32778822)
PreventionGenetics, part of Exact Sciences	RCV004543676	SCV004800608	likely pathogenic	TTN-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The TTN c.64673-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the A-band region of the TTN protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate the adjacent exon is commonly included in TTN mRNA transcripts (PSI of 91%-100%, Roberts et al. 2015. PubMed ID: 25589632; https://www.cardiodb.org/titin/titin_exon.php?id=311). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts et al. 2015. PubMed ID: 25589632; Herman et al. 2012. PubMed ID: 22335739). Many cases of severe 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 et al. 2013. PubMed ID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID:27796757; Ge et al. 2019. PubMed ID: 31053406; Oates et al. 2018. PubMed ID: 29691892; Bryen et al. 2020. PubMed ID: 31660661). In summary, we classify this variant as likely pathogenic. Of note, this variant is considered likely pathogenic for increased risk of TTN-related cardiac disorders, and also for autosomal recessive severe congenital titinopathies when in the presence of an additional loss-of-function TTN variant.