ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.93396_93400del (p.Ala31133_Trp31134insTer) (rs886044536)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000520427 SCV000345305 likely pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing
Invitae RCV000462155 SCV000542838 likely pathogenic Dilated cardiomyopathy 1G 2016-11-08 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 339 of the TTN mRNA (c.93396_93400delAGCTT), causing a frameshift at codon 31134. This creates a premature translational stop signal (p.Trp31134*) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of the TTN gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx RCV000520427 SCV000619669 pathogenic not provided 2019-10-03 criteria provided, single submitter clinical testing Nonsense variant located in the A-band region of TTN predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31618753)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175501 SCV001339102 likely pathogenic Cardiomyopathy 2020-03-10 criteria provided, single submitter clinical testing Variant summary: TTN c.85692_85696delAGCTT (p.Trp28566X) 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 commonly known mechanisms for disease. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (PMID: 22335739, PMID: 24503780) and/or are located in an exon that is highly expressed in the heart (PMID: 25589632), which is the case for the c.85692_85696delAGCTT variant. The variant was absent in 248534 control chromosomes (gnomAD). To our knowledge, no occurrence of c.85692_85696delAGCTT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001377770 SCV001575191 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-09-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Trp31134*). 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 not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 290698). 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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