Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Cardiovascular Biomedical Research Unit, |
RCV000209202 | SCV000189789 | likely pathogenic | Primary dilated cardiomyopathy | 2014-10-08 | criteria provided, single submitter | research | This TTN truncating variant (TTNtv) was identified in two individuals in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. |
| Labcorp Genetics |
RCV001068680 | SCV001233805 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-07-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as 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: 223385). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy and autosomal dominant dilated cardiomyopathy (PMID: 29961767; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg26331*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Clinical Genetics Laboratory, |
RCV004696875 | SCV005198901 | pathogenic | not provided | 2023-09-19 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV004786562 | SCV005400006 | pathogenic | Dilated cardiomyopathy 1G | 2024-10-11 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature termination codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (1 heterozygote, 0 homozygote). (SP) 0600 - Variant is located in the annotated A-band and the exon has a PSI score of 100% (PMID: 25589632). (I) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical diagnostic laboratories and has been reported in two families with DCM (ClinVar; PMID: 30354343). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been reported to segregated with family members with DCM, however it should be noted that unaffected family members were also found to carry the variant (PMID: 30354343). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Zebrafish models homozygous for our variant had severe cardiac dysmorphogenesis and premature death while zebrafish models heterozygous for our variant spontaneously developed DCM in adulthood (PMID: 30354343). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |