Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001377487 | SCV001574828 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser33896*) 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 premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 1066477). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235567 | SCV003934138 | pathogenic | Primary familial dilated cardiomyopathy | 2023-05-23 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.93983C>A (p.Ser31328X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246766 control chromosomes. To our knowledge, no occurrence of c.93983C>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in an exon that is highly expressed in the heart (PMID: 25589632). Based on the evidence outlined above, the variant was classified as pathogenic. |