ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.105485G>A (p.Trp35162Ter) (rs886042795)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000579111 SCV000337133 uncertain significance not provided 2015-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000579111 SCV000680626 likely pathogenic not provided 2017-08-24 criteria provided, single submitter clinical testing The W33521X variant in the TTN gene has not been reported as a pathogenic variant or a benign polymorphism to our knowledge. W33521X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. The W33521X variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, other truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). Furthermore, W33521X is not located in the A-band region of titin, where the majority of truncating mutations associated with dilated cardiomyopathy (DCM) have been reported (Herman et al., 2012).Therefore, based on the currently available information, we classify this variant as likely pathogenic.
Invitae RCV001377585 SCV001574955 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-01-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Trp35162*). 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 individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 284113). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473), but have not been definitively shown to cause cardiomyopathy (PMID: 25589632). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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