ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: 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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000663411 SCV000786699 uncertain significance Autosomal recessive 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 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu11945Argfs*6) in the TTN gene. 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, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with limb girdle weakness and/or skeletal muscle disorders (PMID: 29435569, 32528171; Invitae). This variant has been reported in individual(s) with dilated cardiomyopathy (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 548989). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.

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