Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000184327 | SCV000236952 | pathogenic | not provided | 2023-04-20 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 26315439, 30609409, 22335739) |
| Laboratory for Molecular Medicine, |
RCV000608012 | SCV000731968 | likely pathogenic | Centronuclear myopathy | 2018-02-22 | criteria provided, single submitter | clinical testing | The p.Ala21426X (NM_133432.3 c.64276_64282delinsTA) variant in TTN (also reporte d as c.67057_67063delGCATATGinsTA p.Ala22353fs in the literature) has been prev iously reported in 1 heterozygous proband with dilated cardiomyopathy (DCM) and segregated with disease in 10 family members (7 confirmed to have the variant an d 3 obligate carriers) (Herman 2012). This variant has also been reported as pat hogenic in ClinVar (ClinVar#202465; NM_001256850.1: p.Ala22353Terfs), and was ab sent from large population studies, though the ability of these studies to accur ately detect indels may be limited. This variant leads to a premature terminatio n codon at position 21426, which is predicted to lead to a truncated or absent p rotein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Robe rts 2015), both of which are true for this variant. In addition, pathogenic vari ants in TTN, when found on both copies of the gene, are associated with recessiv e centronuclear myopathy. In summary, this variant meets criteria to be classi fied as pathogenic for DCM in an autosomal dominant manner based upon a predicte d null effect and its segregation in affected individuals, as well as likely pat hogenic for centronuclear myopathy in a recessive manner. |
| Laboratory for Molecular Medicine, |
RCV000611832 | SCV000731969 | pathogenic | Primary dilated cardiomyopathy | 2018-02-22 | criteria provided, single submitter | clinical testing | The p.Ala21426X (NM_133432.3 c.64276_64282delinsTA) variant in TTN (also reporte d as c.67057_67063delGCATATGinsTA p.Ala22353fs in the literature) has been prev iously reported in 1 heterozygous proband with dilated cardiomyopathy (DCM) and segregated with disease in 10 family members (7 confirmed to have the variant an d 3 obligate carriers) (Herman 2012). This variant has also been reported as pat hogenic in ClinVar (ClinVar#202465; NM_001256850.1: p.Ala22353Terfs), and was ab sent from large population studies, though the ability of these studies to accur ately detect indels may be limited. This variant leads to a premature terminatio n codon at position 21426, which is predicted to lead to a truncated or absent p rotein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Robe rts 2015), both of which are true for this variant. In addition, pathogenic vari ants in TTN, when found on both copies of the gene, are associated with recessiv e centronuclear myopathy. In summary, this variant meets criteria to be classi fied as pathogenic for DCM in an autosomal dominant manner based upon a predicte d null effect and its segregation in affected individuals, as well as likely pat hogenic for centronuclear myopathy in a recessive manner. |