ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.40634-1G>A

gnomAD frequency: 0.00001  dbSNP: rs749062863
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000420057 SCV000536380 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTN gene. The c.35711-1 G>A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server). The c.35711-1 G>A variant is predicted to destroy the canonical splice acceptor site in intron 170 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. However, other truncating TTN variants have been reported in approximately 3% of control alleles and the c.35711-1 G>A variant is not 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV001865402 SCV002244876 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2021-09-26 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. 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: 393030). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (rs749062863, ExAC 0.01%). This sequence change affects an acceptor splice site in intron 220 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. 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).

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