Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000527106 | SCV000642677 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2022-03-05 | 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). ClinVar contains an entry for this variant (Variation ID: 466814). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser4509Leufs*21) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786260 | SCV000925011 | uncertain significance | not provided | 2017-10-19 | no assertion criteria provided | provider interpretation | p.Ser4509Leufs*21 (c.13525delT) in the I band of the TTN gene (NM_001267550.2; chr2-179604435-A-) We have seen this in a patient in our center with DCM who also has an RBM20 missense variant. SCICD Classification: variant of uncertain significance based on lack of case data and location of the variant in the I band. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): not reported with disease before per lab report and cardiodb.org. ClinVar: not present Cases in the literature: none reported Population data: The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 100x whereas in exomes it is 35x. Per the TTN tool at cardiodb.org, LRG exon number is 49 (this is a meta exon number system created to include all TTN exons and preferred in reporting variants), N2BA transcript is 46. It is located in the I-band, 100% spliced in to cardiac isoforms, in an Ig-like domain. Other variants in the same exon has previously been reported in patients with DCM. TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN truncating variants are seen in 13-30% of people with DCM and are thought to confer pathogenesis in a dominant-negative fashion (Herman et al 2012, Roberts et al 2015). There is strong evidence implicating them in the pathogenesis of DCM, though it remains unclear whether they are confer risk in a Mendelian or multifactorial fashion (Watkins et al 2015). Furthermore, each individual TTN variant must be evaluated carefully for potential pathogenicity given the presence of truncating TTN variants in 1-3% of the general population (Herman et al 2012, Roberts et al 2015) and the failure of some TTN truncating variants to segregate in DCM families (Norton et al 2013). TTN truncating variants located in the A-band and in exons frequently included in the cardiac isoforms N2B and N2BA are enriched in DCM patients versus controls (Roberts et al 2015). However, it is notable that when focusing these variants (A-band, frequently included N2B, N2BA), 15% of DCM cases and 1% of a normal sample have such variants (Roberts et al 2015). Roberts et al (2015) estimated that when such a variant is found in a proband there is a 93% chance it is disease-causing. |