ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.42946+1G>T

dbSNP: rs1553741531
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498935 SCV000589737 likely pathogenic not provided 2016-02-02 criteria provided, single submitter clinical testing Although the c.38023+1 G>T likely pathogenic variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, it destroys the canonical splice donor site in intron 182 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.38023+1 G>T is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, c.38023+1 G>T was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.38023+1 G>T in the TTN gene is expected to be pathogenic
Invitae RCV001248235 SCV001421705 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-03-09 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 432063). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 232 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein.

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