ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.59926+1G>A

dbSNP: rs553526525
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000696084 SCV000824631 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-09-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 302 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs553526525, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739, 29057560). It has also been observed to segregate with disease in related individuals. This variant is also known as c.55003+1G>A. ClinVar contains an entry for this variant (Variation ID: 574210). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV001528301 SCV002496222 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing Variant reported heterozygous in multiple unrelated patients with dilated cardiomyopathy (Herman et al., 2012; van den Hoogenhof et al., 2018; Marschall et al., 2019; Nguyen et al., 2021); Not observed at a 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 titinopathies (Herman et al., 2012); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29650543, 23975875, 29057560, 30847666, 32880476, 37183561, 36344503, 31112426, 32964742, 31737537, 22335739, 34011823, 33662488)
CeGaT Center for Human Genetics Tuebingen RCV001528301 SCV004011264 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing TTN: PVS1:Strong, PM1, PM2, PS4:Moderate
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486921 SCV004240060 pathogenic Cardiomyopathy 2022-09-01 criteria provided, single submitter clinical testing
KTest Genetics, KTest RCV001594401 SCV001499991 pathogenic Dilated cardiomyopathy 1G no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528301 SCV001739819 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001528301 SCV001930986 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001528301 SCV001959765 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV001528301 SCV001978888 pathogenic not provided no assertion criteria provided clinical testing

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