Submissions for variant NM_001267550.2(TTN):c.76278G>A (p.Trp25426Ter)

dbSNP: rs1064794060

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481430	SCV000567700	pathogenic	not provided	2015-08-24	criteria provided, single submitter	clinical testing	The W23785X variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign polymorphism, to our knowledge. W23785X is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, W23785X is located in the A-band region of titin, where the majority of truncating variants associated with DCM have been reported (Herman et al., 2012). Furthermore, W23785X was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, W23785X in the TTN gene is interpreted as a pathogenic variant.
Invitae	RCV003766674	SCV004580218	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp25426*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10566 amino acid(s) of the TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 31112426, 31983221). ClinVar contains an entry for this variant (Variation ID: 419714). 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). 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.