ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.29245C>T (p.Gln9749Ter) (rs746721983)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000517677 SCV000236820 likely pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing The Q9432X variant in the TTN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q9432X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q9432X as a likely pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000195104 SCV000249248 pathogenic Myopathy 2015-04-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000517677 SCV000616050 likely pathogenic not provided 2016-08-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778578 SCV000914882 uncertain significance TTN-Related Disorders 2018-11-14 criteria provided, single submitter clinical testing The TTN c.25513C>T (p.Gln8505Ter) variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders.
Invitae RCV001066897 SCV001231920 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-05-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Gln9749*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs746721983, ExAC 0.001%). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 202356). 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). 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.

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