ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.59201_59202del (p.Pro19734fs) (rs752948913)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479171 SCV000567027 likely pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing Although the c.54278_54279delCT variant in the TTN gene has not been reported to our knowledge, this deletion causes a shift in reading frame starting at codon Proline 18093, changing it to an Arginine, andcreating a premature stop codon at position 5 of the new reading frame, denoted p.Pro18093ArgfsX5. Thisdeletion is expected to result in either an abnormal, truncated protein product or loss of protein from thisallele through nonsense-mediated mRNA decay. Other frameshift variants in the TTN gene have beenreported in HGMD in association with cardiomyopathy (Stenson P et al., 2014). Furthermore, thec.54278_54279delCT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 100 Genomes Consortium et al., 2015; Exome Variant Server). Moreover, c.54278_54279delCT is located in the A-band region of titin, where the majority of truncating variants associated with DCM have been reported (Herman D et al., 2012). In summary, c.54278_54279delCT in the TTN gene is interpreted as a likely pathogenic variant.
Blueprint Genetics RCV000479171 SCV000927260 likely pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing
Invitae RCV000823812 SCV000964682 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-11-27 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Pro19734Argfs*5). 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 (rs752948913, ExAC 0.001%). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 419310). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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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