ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.45307C>T (p.Arg15103Ter) (rs397517580)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000642772 SCV000764459 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-01-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg15103*). 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 been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 46986). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040256 SCV000063947 likely pathogenic Primary dilated cardiomyopathy 2017-08-25 criteria provided, single submitter clinical testing The p.Arg12535X variant in TTN has been identified by our laboratory in 1 indivi dual with DCM and segregated with disease in 2 affected relatives, including one obligate carrier. This variant was absent from large population studies. This n onsense variant leads to a premature termination codon at position 12535, which is predicted to lead to a truncated or absent protein. Nonsense and other trunca ting variants in TTN are strongly associated with DCM if they impact the exons e ncoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that i s highly expressed in the heart (Roberts 2015). The p.Arg12535X variant is locat ed in the I-band in the highly expressed exon 194. In summary, although addition al studies are required to fully establish its clinical significance, the p.Arg1 2535X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786251 SCV000925001 uncertain significance not provided 2017-09-22 no assertion criteria provided provider interpretation

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