ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.104771C>A (p.Ser34924Ter)

dbSNP: rs1559003939
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000706582 SCV000835641 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser34924*) in the TTN gene. 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 (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32815318). ClinVar contains an entry for this variant (Variation ID: 582494). 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). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375607 SCV001572515 likely pathogenic Primary familial dilated cardiomyopathy 2021-04-09 criteria provided, single submitter clinical testing Variant summary: TTN c.97067C>A (p.Ser32356X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are known mechanisms of disease for variants located in exons that are highly expressed in cardiac tissues. The variant, c.97067C>A, is located in the M-band region and has been reported to be highly expressed in cardiac isoforms (PSI=100%; cardiodb.org); therefore truncating mutations in this region may be associated with disease. The variant was absent in 248540 control chromosomes (gnomAD). c.97067C>A has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy (under transcript NM_001267550 as c.104771C>A, p.Ser34924X) . This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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