ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.71602C>T (p.Arg23868Ter) (rs397517689)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000208052 SCV000064262 pathogenic Primary dilated cardiomyopathy 2017-09-22 criteria provided, single submitter clinical testing The p.Arg21300X variant in TTN has been identified by our laboratory in 2 adults with DCM. In one family, it segregated with disease in 7 affected relatives (in cluding 3 obligate carriers). This variant has also been identified in 1/110914 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs397517689) and has been reported in ClinVar (Variation ID: 473 01). This nonsense variant leads to a premature termination codon at position 21 300, which is predicted to lead to a truncated or absent protein. Nonsense and o ther truncating variants in TTN are strongly associated with DCM, particularly i f they are located in the exons encoding for the A-band region of the protein (H erman 2012, Pugh 2014), where this variant is located. In summary, this variant meets criteria to be classified as pathogenic for DCM in an autosomal dominant m anner based on segregation studies and the predicted effect of this variant on t he protein. ACMG/AMP Criteria applied: PVS1; PP1_Strong; PM2.
GeneDx RCV000184258 SCV000236880 pathogenic not provided 2015-06-12 criteria provided, single submitter clinical testing The R22227X mutation in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge, but has been observed in one other unrelated individual tested for DCM at GeneDx. R22227X 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 D et al., 2012). However, R22227X is located in the A band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, R22227X was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in DCM,DCM-CRDM panel(s).
Blueprint Genetics RCV000208052 SCV000264283 likely pathogenic Primary dilated cardiomyopathy 2015-07-01 criteria provided, single submitter clinical testing
Invitae RCV000542963 SCV000642461 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 23868 (p.Arg23868*) of the TTN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with peripartum cardiomyopathy and dilated cardiomyopathy (PMID: 26735901, 28416588). ClinVar contains an entry for this variant (Variation ID: 47301). This variant is found in the A-band of this gene. 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). Truncating variants in TTN have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623243 SCV000740484 pathogenic Familial dilated cardiomyopathy 2017-02-16 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768934 SCV000900307 pathogenic Cardiomyopathy 2016-12-07 criteria provided, single submitter clinical testing

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