Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000533443 | SCV000642477 | likely pathogenic | Dilated cardiomyopathy 1G | 2017-06-05 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the TTN (p.Leu31395Serfs*11). It is expected to result in a disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786245 | SCV000924990 | likely pathogenic | not provided | 2017-11-10 | no assertion criteria provided | provider interpretation | p.Leu31395Serfs*11 (c.94182_94183insAGCAGCT) in exon 339 of the TTN gene (NM_001267550.2; chr2-179403451--AGCTGCT) SCICD Classification: likely pathogenic variant based on its location in the TTN gene: truncating variants in the A-band that are 100% spliced in are likely causative of disease. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TTN: 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). Region-level evidence: Truncating variants in the A-band of titin are present in patients with DCM than in controls. The genomic coordinates for this variant are chr2-179403451--AGCTGCT (hg19). Per the TTN tool at cardiodb.org, LRG exon number is 338 (this is a meta exon number system created to include all TTN exons and preferred in reporting variants), N2BA transcript is 288. It is located in the A-band, 100% spliced in to cardiac isoforms, in a fibronectin type domain domain. Another variant in the same exon has not previously been reported in patients with DCM. Case data (not including our patient): none ClinVar: not present Cases in the literature: none reported Segregation data: none reported Functional data: none reported Conservation data: The leucine at codon 31395 is not conserved across species. Nearby pathogenic variants at this codon or neighboring codons: none Population data: There is no variation at codon 31395 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 82.6x whereas in exomes it is 34.1x. |