ClinVar Miner

Submissions for variant NM_001256850.1(TTN):c.39349C>T (p.Arg13117Ter) (rs140743001)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769014 SCV000900387 uncertain significance Cardiomyopathy 2016-05-20 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000495986 SCV000584180 likely pathogenic Dilated cardiomyopathy 1G 2016-11-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000623485 SCV000339614 uncertain significance not provided 2016-02-12 criteria provided, single submitter clinical testing
GeneDx RCV000623485 SCV000236835 likely pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing The R13117X variant in the TTN gene has been reported previously in association with DCM; however, detailed clinical information and segregation data were not provided (Walsh et al., 2017). This variant is classified as a variant of uncertain significance and a likely pathogenic variant by several clinical laboratories in ClinVar (SCV000272648.1, SCV000339614.2, SCV000643183.1, SCV000584180.1; Landrum et al., 2016). In addition, the R13117X variant has been observed in several other individuals referred for DCM genetic testing at GeneDx; however, only one individual harbored no co-occurring cardiogenetic variants. The R13117X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R13117X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). Nevertheless, the R13117X variant is located in one of the constitutive exons in the distal I-band region and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also associated with DCM (Schafer et al., 2017; Deo et al., 2017).
Invitae RCV000538338 SCV000643183 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-05-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in exon 239 coding for the I-Band of the TTN mRNA at codon 14758 (p.Arg14758*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs140743001, ExAC 0.002%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202367). In summary, although this is a rare truncating variant, truncating variants affecting the I-Band have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (PMID: 26701604, 22335739). Furthermore, this truncation is located outside of a clinically relevant region of the TTN gene (PMID: 25589632). For these reasons it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000599630 SCV000272648 likely pathogenic Primary dilated cardiomyopathy 2016-06-03 criteria provided, single submitter clinical testing The p.Arg12190X variant in TTN has been identified by our laboratory in 1 Caucasian individual with DCM and 1 Caucasian individual with LVNC (LMM data). This variant has also been identified in 1/67564 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140743001). This nonsense variant leads to a premature termination codon at position 12190, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Arg12190X variant is located in I-band in the highly expressed exon 188. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg12190X variant is likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623485 SCV000740470 likely pathogenic not provided 2016-07-30 criteria provided, single submitter clinical testing

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