Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000599404 | SCV000710092 | likely pathogenic | not provided | 2018-07-12 | criteria provided, single submitter | clinical testing | The c.46993_46999delGGTGAAG likely pathogenic variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. This variant causes a shift in reading frame starting at codon glycine 15665, changing it to a phenylalanine, and creating a premature stop codon at position 11 of the new reading frame, denoted p.Gly15665PhefsX11. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, the c.46993_46999delGGTGAAG variant is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, the c.46993_46999delGGTGAAG variant is not observed in large population cohorts (Lek et al., 2016). |
| Ambry Genetics | RCV004024878 | SCV005020878 | likely pathogenic | Cardiovascular phenotype | 2023-11-02 | criteria provided, single submitter | clinical testing | The c.24721_24727delGGTGAAG variant, located in coding exon 100 of the TTN gene, results from a deletion of 7 nucleotides at nucleotide positions 24721 to 24727, causing a translational frameshift with a predicted alternate stop codon (p.G8241Ffs*11). 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. |