ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.47314C>T (p.Arg15772Ter)

dbSNP: rs2154209202
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376746 SCV001573907 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg15772*) 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 individuals with autosomal dominant dilated cardiomyopathy (PMID: 27532257, 33106378; Invitae). ClinVar contains an entry for this variant (Variation ID: 1065903). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV002282533 SCV002571503 likely pathogenic not provided 2022-02-22 criteria provided, single submitter clinical testing Reported in association with cardiomyopathy (Walsh et al., 2017; Mazzarotto et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant TTN-related titinopathies (Herman et al., 2012); Nonsense 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; This variant is associated with the following publications: (PMID: 31983221, 27532257, 22335739)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003331139 SCV004038524 pathogenic Primary familial dilated cardiomyopathy 2023-08-09 criteria provided, single submitter clinical testing Variant summary: TTN c.39610C>T (p.Arg13204X) 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 is a commonly known mechanism for disease. Nonsense, frameshift, and canonical splice-site variants in TTN are strongly associated with DCM when they affect exons encoding for the A-band region (PMIDs: 22335739, 24503780) and/or exons constitutively expressed (proportion spliced in [PSI]>0.9) in the primary cardiac isoforms (PMIDs: 25589632, 31216868, 32964742, 27869827), which is the case forthis variant (I band with a PSI score of 100%). The variant was absent in 247508 control chromosomes (gnomAD). c.39610C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Vissing_2021). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33106378). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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