Submissions for variant NM_001267550.2(TTN):c.90495G>A (p.Trp30165Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV003315109	SCV004014667	likely pathogenic	Dilated cardiomyopathy 1G	2023-04-24	criteria provided, single submitter	clinical testing	The TTN c.90495G>A (p.Trp30165Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is located in exon 335 of the meta transcript of titin within the A-band, which is highly expressed in cardiac tissue (PMID: 25589632). In a meta-analysis of TTN truncating variants in DCM patients and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio 40.6-61.1) (PMID: 27869827). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.90495G>A (p.Trp30165Ter) variant is classified as likely pathogenic for dilated cardiomyopathy.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003777286	SCV004584455	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp30165*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. 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: 2572995). 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.