Submissions for variant NM_001267550.2(TTN):c.1245+3A>G

gnomAD frequency: 0.00003  dbSNP: rs757221300

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209716	SCV000189723	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001234919	SCV001407580	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs757221300, gnomAD 0.007%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 33106378). ClinVar contains an entry for this variant (Variation ID: 223251). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 Z band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002390561	SCV002672562	uncertain significance	Cardiovascular phenotype	2023-04-18	criteria provided, single submitter	clinical testing	The c.1245+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 6 in the TTN gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been detected in a dilated cardiomyopathy cohort and in the Framingham Heart Study cohort; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Vissing CR et al. J Med Genet. 2021 Dec;58(12):832-841). In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002494546	SCV002797060	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV005222831	SCV005870262	uncertain significance	not provided	2024-08-20	criteria provided, single submitter	clinical testing	Located in the Z-disk region of titin, whereas the majority of truncating pathogenic variants associated with DCM have been reported in the A-band region or other constitutive exons in the I-band region of the TTN gene (PMID: 27625338, 27869827, 22335739); In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; In silico analysis indicates that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 33106378, 25589632, 27625338, 27869827, 22335739)