ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.35678C>G (p.Thr11893Ser)

gnomAD frequency: 0.00001  dbSNP: rs750832804
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000532364 SCV000643045 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-06-28 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001004945 SCV001164469 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-12-03 criteria provided, single submitter research The heterozygous p.Thr11893Ser variant in TTN was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a likely pathogenic variant and in an individual with LGMD increases the likelihood that the p.Thr11893Ser variant is pathogenic. This variant has been identified in 0.008833% (3/33964) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750832804). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional computational tools suggest this variant may impact splicing, resulting in a frameshift and early termination codon. In summary, the clinical significance of p.Thr11893Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_Supporting, BP4 (Richards 2015).
GeneDx RCV001785656 SCV002027931 uncertain significance not provided 2024-12-06 criteria provided, single submitter clinical testing Observed with a second TTN variant in patients with hypotonia, muscle weakness, and/or additional clinical features of a TTN-related skeletal myopathy referred for genetic testing at GeneDx and in published literature; it is not known if the variants are on the same allele (in cis) or on opposite alleles (in trans) in some cases (PMID: 32403337); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32403337)

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