Submissions for variant NM_001267550.2(TTN):c.48460+5G>A

gnomAD frequency: 0.00020  dbSNP: rs374413644

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209156	SCV000189756	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in four individuals 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154940	SCV000204622	uncertain significance	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.40756+5G>A variant in TTN has been identified in 1 African American individual with DCM. It has also been identified in 11/23996 of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374413644). This variant has also been reported in ClinVar (Variation ID:178208). This variant is located in intron 207 in the 5' splice region. Computational tools suggest an impact to splicing; however, this information is not predictive enough to determine pathogenicity. Splice and other truncating variants in TTN are strongly associated with DCM and the majority occur in exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), where this variant is located. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.40756+5G>A variant is uncertain.
Invitae	RCV000477507	SCV000542250	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 258 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 (rs374413644, gnomAD 0.05%). 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: 178208). 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 A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). 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.
GeneDx	RCV000498511	SCV000589785	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739, 25589632)
Ambry Genetics	RCV002415663	SCV002726092	uncertain significance	Cardiovascular phenotype	2023-02-15	criteria provided, single submitter	clinical testing	The c.21265+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 85 in the TTN gene. This variant (referred to as c.48460+5G>A) has been detected in individuals from a community-based cohort; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484928	SCV002781414	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	2022-04-29	criteria provided, single submitter	clinical testing