ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.35828dup (p.Glu11945Argfs) (rs765879488)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000663411 SCV000786699 uncertain significance Limb-girdle muscular dystrophy, type 2J criteria provided, single submitter research The heterozygous p.Glu11945fs variant in TTN has been identified in the compound heterozygous state by our project in one individual with Limb Girdle Muscular Dystrophy. This variant has not been reported in the literature but compound heterozygous loss of function variants have been previously described in individuals with Limb Girdle Muscular Dystrophy (source: ClinVar). This varint has been identified in <0.01% (2/70872) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765879488). AAlthough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain.
Invitae RCV000704886 SCV000833858 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-08-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Glu11945Argfs*6). 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 (rs765879488, ExAC 0.009%). This variant has not been reported in the literature in individuals with TTN-related disease. 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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