Submissions for variant NM_001267550.2(TTN):c.67058-1G>C

dbSNP: rs756715989

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184388	SCV000237013	pathogenic	not provided	2014-10-16	criteria provided, single submitter	clinical testing	c.62135-1 G>C: IVS267-1 G>C in intron 267 of the TTN gene (NM_001256850.1) Truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM (Herman D et al., 2012). However, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). TTN mutations may also be associated with congenital cardiac and skeletal myopathies, hereditary myopathy with early respiratory failure, tibial muscular dystrophy, and limb-girdle muscular dystrophy (Lange S et al., 2005; Hackman P et al., 2002; Carmignac V et al., 2007; Hackman P et al., 2008). Although the c.62135-1 G>C mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice acceptor site in intron 267 and is predicted to cause abnormal gene splicing. The mutation 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 truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.62135-1 G>C is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.62135-1 G>C in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s).
Ambry Genetics	RCV004020246	SCV005020568	uncertain significance	Cardiovascular phenotype	2023-12-26	criteria provided, single submitter	clinical testing	The c.39863-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 145 of the TTN gene. Exon 146 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 may 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.