ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.75328C>T (p.Arg25110Ter) (rs794729382)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184390 SCV000237015 pathogenic not provided 2018-02-07 criteria provided, single submitter clinical testing The R23469X pathogenic variant in the TTN gene has not been reported previously as a disease-causing pathogenic variant or as a benign variant, to our knowledge. However, this variant has previously been identified in other unrelated individuals referred for DCM genetic testing at GeneDx. R23469X is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, R23469X 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 R23469X variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae RCV000532259 SCV000642463 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-06-15 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg25110*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202521). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000184390 SCV000924983 likely pathogenic not provided 2017-09-11 no assertion criteria provided provider interpretation Given that this is a rare, truncating variant in the A-band of TTN, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: 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 variants are the most common cause of idiopathic dilated cardiomyopathy. Variant type: Truncating variant in the A-band. 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. Review of the p.Arg25510* truncating variant in cardiodb.org: The genomic coordinates for this variant are chr2: 179435531 (hg19). Per the TTN tool at cardiodb.org, LRG exon number is 326 (this is a meta exon number system created to include all TTN exons and preferred in reporting variants), N2BA transcript is 276. It is located in the A-band and is 100% spliced in to cardiac isoforms. Another variant in the same exon has previously been reported in more than 50 cases of DCM. Total number of cases (not including our patient): at least 1: -ClinVar: present -Classified as: likely pathogenic -Number of individuals: unknown -Submitted by: GeneDx -Last reviewed: March 2017 -Case data: There is no published literature available to review. Prevalence in the general population: Per varsome.com it is not present in gnomAD, which has >140,000 samples. Median coverage in exome samples is 93.9x and in genome samples is 34.3x.

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