ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.44272C>T (p.Arg14758Ter) (rs140743001)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000623485 SCV000236835 likely pathogenic not provided 2020-08-06 criteria provided, single submitter clinical testing Reported in association with DCM and familial atrial fibrillation (Walsh et al., 2017; Ahlberg et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay; Reported in ClinVar (ClinVar Variant ID# 202367; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 22335739, 24503780, 30333491, 31737537)
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 Caucas ian individual with DCM and 1 Caucasian individual with LVNC (LMM data). This va riant has also been identified in 1/67564 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140743001). Th is nonsense variant leads to a premature termination codon at position 12190, wh ich is predicted to lead to a truncated or absent protein. Nonsense and other tr uncating 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 i n 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, alth ough additional studies are required to fully establish its clinical significanc e, the p.Arg12190X variant is likely pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000623485 SCV000339614 uncertain significance not provided 2016-02-12 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
Invitae RCV000538338 SCV000643183 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-10-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (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%). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 202367). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769014 SCV000900387 uncertain significance Cardiomyopathy 2016-05-20 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000623485 SCV001740360 likely pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000623485 SCV001931708 likely pathogenic not provided no assertion criteria provided clinical testing

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