ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.61876C>T (p.Arg20626Ter) (rs72646846)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211745 SCV000064136 likely pathogenic Primary dilated cardiomyopathy 2019-03-08 criteria provided, single submitter clinical testing The p.Arg18058X variant in TTN has been identified in >20 individuals with DCM and segregated with disease in 3 affected individuals from 3 families (Herman 2012, Merlo 2013, unpublished data from GeneDx, Ambry, Invitae, and LMM). It has also been identified in 6 individuals with centronuclear myopathy or who underwent genetic testing for neuromuscular disorders (Elahi 2018, EGL pers. comm., Invitae pers. comm.). This variant has been identified in 0.16% (17/10348) of Ashkenazi Jewish, 1/128284 European, and 1/35320 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although the frequency in the Ashkenazi Jewish population is higher than expected for a pathogenic variant based on the disease prevalence of DCM, a comparison of the prevalence of this variant in the gnomAD database to DCM patients (LMM data only) shows that it is statistically enriched in the patient population (OR=23.4, p<0.0001). This nonsense variant leads to a premature termination codon at position 18058, which is predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band, where this variant is located (Herman 2012, Pugh 2014). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM based on the predicted loss of function impact, enrichment in affected individuals, and segregation studies. ACMG/AMP criteria applied: PVS1_Strong, PP1, PS4_Supporting.
GeneDx RCV000184247 SCV000236869 likely pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The R18985X variant in the TTN gene has been reported previously in two unrelated families with dilated cardiomyopathy (DCM), and was absent from 249 control individuals (Herman et al., 2012; Merlo et al., 2013). Additionally, the R18985X variant has been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The R18985X variant is observed in 16/10,144 alleles (0.15%) from individuals of Ashkenazi Jewish background in the gnomAD dataset (Lek et al., 2016). The R18985X variant 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, R18985X 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). In summary, R18985X in the TTN gene is interpreted as a likely pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000184247 SCV000339164 likely pathogenic not provided 2016-02-18 criteria provided, single submitter clinical testing
Invitae RCV000642745 SCV000764432 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-12-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg20626*). It is expected to expected to result in a disrupted protein product. This variant is present in population databases (rs72646846, ExAC 0.01%). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 22335739, 24119082). ClinVar contains an entry for this variant (Variation ID: 47175). 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). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768966 SCV000900339 likely pathogenic Cardiomyopathy 2018-07-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000184247 SCV001249867 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256787 SCV001433233 pathogenic Dilated cardiomyopathy 1A 2019-01-15 criteria provided, single submitter clinical testing

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