ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.105854dup (p.Pro35286fs)

dbSNP: rs2468381753
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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 RCV003226062 SCV003922158 likely pathogenic Early-onset myopathy with fatal cardiomyopathy 2023-05-02 criteria provided, single submitter curation The heterozygous p.Pro35286ThrfsTer13 variant in TTN was identified by our study, in the compound heterozygous state with a likely pathogenic variant (NC_000002.12:g.178640613del), in one individual with Salih myopathy. This individual also carried a likely pathogenic variant (NC_000002.12:g.178640613del); however, the phase of these variants is unknown at this time. The p.Pro35286ThrfsTer13 variant in TTN has not been previously reported in individuals with Salih myopathy. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 35286 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive Salih myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Salih myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).
Solve-RD Consortium RCV005102422 SCV005849077 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-09-01 no assertion criteria provided research This indel leads to a frameshift in exon 308 of TTN, which is ubiquitously expressed exon in TTN (PMID: 29598826). The variant was identified in a patient with suspected titinopathy, and the patient carries another frameshift variant (c.40652del) in trans. Frameshift variants have been extensively described as disease-causing in titinopathies. The variant was confirmed as disease-causing by referring clinical team.

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