Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV004018318 | SCV004847507 | likely pathogenic | Primary dilated cardiomyopathy | 2013-09-18 | criteria provided, single submitter | clinical testing | The Gln24762X variant in TTN has been reported in 1 adult with DCM, segregated with disease in 2 affected relative (C. Seidman, personal communication) and has not been identified in large population studies. This nonsense variant leads to a premature termination codon at position 24762, which is predicted to lead to a truncated or absent protein. Truncating variants in TTN are strongly associated with DCM and the majority occur in the A-band (Herman 2012, LMM unpublished data), where this variant is located. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. |
Ambry Genetics | RCV004372004 | SCV005020758 | pathogenic | Cardiovascular phenotype | 2023-09-21 | criteria provided, single submitter | clinical testing | The p.Q18265* pathogenic mutation (also known as c.54793C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 54793. This changes the amino acid from a glutamine to a stop codon within coding exon 153. 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 has been detected in probands with dilated cardiomyopathy and was indicated to segregate with disease in one family (Herman DS et al. N Engl J Med, 2012 Feb;366:619-28). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |