Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000155909 | SCV000205620 | likely pathogenic | Primary dilated cardiomyopathy | 2013-08-11 | criteria provided, single submitter | clinical testing | The Tyr27924X variant in TTN has not been reported in individuals with cardiomyo pathy or in large population studies. This nonsense variant leads to a premature termination codon at position 27924, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly as sociated with DCM and the majority occur in the A-band (Herman 2012, LMM unpubli shed data), where this variant is located. In summary, this variant is likely pa thogenic, though additional studies are required to fully establish its clinical significance. |
Labcorp Genetics |
RCV001040492 | SCV001204068 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-04-22 | 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). ClinVar contains an entry for this variant (Variation ID: 179124). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr30492*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
Ambry Genetics | RCV003162636 | SCV003883315 | likely pathogenic | Cardiovascular phenotype | 2023-01-20 | criteria provided, single submitter | clinical testing | The p.Y21427* variant (also known as c.64281T>G), located in coding exon 163 of the TTN gene, results from a T to G substitution at nucleotide position 64281. This changes the amino acid from a tyrosine to a stop codon within coding exon 163. This exon 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |