Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523807 | SCV000620993 | uncertain significance | not provided | 2017-09-19 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the TTN gene. The c.37675_37676insG variant in the TTN gene has not been reported as a pathogenic or benign variant to our knowledge. This variant causes a shift in reading frame starting at codon methionine 12559, changing it to an serine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Met12559SerfsX8. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. The c.37675_37676insG variant has not been observed in a large population cohort (Exome Variant Server). Other frameshift variants in the TTN gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Nevertheless, the majority of pathogenic variants reported in association with autosomal dominant dilated cardiomyopathy (DCM) are truncating variants in the A-band region of titin, while the clinical significance of variants in the I-band, where c.37675_37676insG occurs, is not well characterized. Furthermore, truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). |
| Laboratory for Molecular Medicine, |
RCV000607920 | SCV000712543 | likely pathogenic | Centronuclear myopathy | 2018-11-13 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Laboratory for Molecular Medicine, |
RCV000611672 | SCV000712544 | likely pathogenic | Primary dilated cardiomyopathy | 2018-11-13 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Invitae | RCV000823984 | SCV000964859 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2018-12-03 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). This variant has not been reported in the literature in individuals with TTN-related disease. This variant is also known in the literature as c.34894_34895insG (p.Met11632Serfs*8). ClinVar contains an entry for this variant (Variation ID: 452205). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Met14200Serfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Ambry Genetics | RCV002404349 | SCV002705885 | likely pathogenic | Cardiovascular phenotype | 2021-06-28 | criteria provided, single submitter | clinical testing | The c.15403_15404insG variant, located in coding exon 58 of the TTN gene, results from an insertion of one nucleotide at position 15403, causing a translational frameshift with a predicted alternate stop codon (p.M5135Sfs*8). This exon is located in the I-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 alteration has been reported, reported as c.34894_34895insG, in a male infant (Ceyhan-Birsoy O et al. Am J Hum Genet, 2019 01;104:76-93). In addition, 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). As such, this alteration is classified as likely pathogenic. |