ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.9610C>T (p.Arg3204Ter) (rs757836789)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726264 SCV000343263 uncertain significance not provided 2016-07-28 criteria provided, single submitter clinical testing
GeneDx RCV000726264 SCV000618718 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing The R3204X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3204X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, the R3204X variant is not located in the A-band nor the M-line region of titin, where the majority of pathogenic truncating variants have been reported.
Illumina Clinical Services Laboratory,Illumina RCV000779289 SCV000915871 uncertain significance TTN-Related Disorders 2018-11-05 criteria provided, single submitter clinical testing The TTN c.9610C>T (p.Arg3204Ter) variant is a stop-gained variant that is predicted to result in an absent or truncated protein. A literature search was conducted for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database, but this frequency is based on one allele only in a region of good sequencing coverage. The variant is therefore presumed to be rare. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, the p.Arg3204Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000822916 SCV000963741 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-07-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg3204*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 288998). 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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