Submissions for variant NM_001267550.2(TTN):c.48638+5G>T

dbSNP: rs397517594

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040293	SCV000063984	uncertain significance	not specified	2013-02-25	criteria provided, single submitter	clinical testing	The 40934+5G>T variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), though it may be co mmon in other populations. It is located in the 5' splice region, and computatio nal tools do not provide strong support for or against an impact to splicing. Ad ditional information is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000578677	SCV000681174	likely pathogenic	not provided	2017-11-30	criteria provided, single submitter	clinical testing	The c.43715+5 G>T likely pathogenic variant in the TTN gene has not been reported as a pathogenic or benign to our knowledge. The c.43715+5 G>T variant is not observed in large population cohorts (Lek et al., 2016). This substitution occurs at a nucleotide position that is conserved across species, and in silico splice prediction programs predict this variant results in loss of the natural splice donor site for intron 209 which is predicted to cause abnormal gene splicing. This variant 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 splice site variants in TTN, including additional variants at the +5 position, have been reported in HGMD in association with DCM (Stenson et al., 2014). Although truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012), the c.43715+5 G>T variant is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Nonetheless, in the absence of functional mRNA studies, the physiological consequences of this variant cannot be precisely determined.
Ambry Genetics	RCV002426574	SCV002730289	uncertain significance	Cardiovascular phenotype	2022-03-09	criteria provided, single submitter	clinical testing	The c.21443+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 86 in the TTN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002513563	SCV003201303	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 259 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 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: 47023). 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.