Submissions for variant NM_001267550.2(TTN):c.64742G>A (p.Trp21581Ter)

dbSNP: rs1057523344

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427280	SCV000531612	likely pathogenic	not provided	2016-09-06	criteria provided, single submitter	clinical testing	The W19940X variant in the TTN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W19940X variant was not observed in approximately 6,100 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 general, truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, W19940X is located in the A-band region of titin, where the majority of pathogenic truncating variants associated with dilated cardiomyopathy have been reported (Herman D et al., 2012). Therefore, we interpret W19940X as a likely pathogenic variant.
Invitae	RCV001221206	SCV001393232	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-05-14	criteria provided, single submitter	clinical testing	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. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 389160). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Trp21581*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.