ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.30511+1G>C

gnomAD frequency: 0.00001  dbSNP: rs879082842
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520831 SCV000619489 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTN gene. The c.29560+1 G>C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant destroys the canonical splice donor site in intron 106 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 splice site variants in the TTN gene have been reported in HGMD in association with TTN-related disorders (Stenson et al., 2014). Furthermore, the c.29560+1 G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, other truncating TTN variants have been reported in approximately 3% of control alleles and c.29560+1 G>C 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). In the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Labcorp Genetics (formerly Invitae), Labcorp RCV001857989 SCV002130351 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-08-14 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: 450866). 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 108 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein.
Fulgent Genetics, Fulgent Genetics RCV002481714 SCV002794268 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-11-04 criteria provided, single submitter clinical testing

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