ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.86387_86391del (p.Arg28796fs)

dbSNP: rs794729354
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184347 SCV000236972 pathogenic not provided 2023-07-07 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22335739)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000768878 SCV000900251 pathogenic Cardiomyopathy 2017-10-27 criteria provided, single submitter clinical testing
Invitae RCV001852392 SCV002147595 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-06-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 202482). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg28796Glnfs*5) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Institute of Human Genetics, Heidelberg University RCV003457650 SCV004185533 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2023-12-11 criteria provided, single submitter clinical testing

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