NM_001844.5(COL2A1):c.1680+1G>A AND Stickler syndrome type 1

Significance: Pathogenic
ClinVar: RCV000018925

Variant: NM_001844.5(COL2A1):c.1680+1G>A

Type: Variant
Allele: NM_001844.5(COL2A1):c.1680+1G>A 32421
Type: single nucleotide variant
Location: Chr12: 47985727 - assembly GRCh38
Chr12: 48379510 - assembly GRCh37
References: OMIM: 120140.0032


Disease: Stickler syndrome type 1


    Freddi et al. (2000) described a novel strategy for screening families with type I Stickler syndrome (STL1; 108300) due to nonsense mutations in the COL2A1 gene, using a modified RNA-based protein truncation test. To overcome the problem of the unavailability of collagen II-producing cartilage cells, they performed RT-PCR on the illegitimate transcripts of accessible cells (lymphoblasts and fibroblasts), which were preincubated with cycloheximide to prevent nonsense mutation-induced mRNA decay. The 5 overlapping RT-PCR fragments covering the COL2A1 coding region were then transcribed and translated in vitro to identify smaller truncated protein products resulting from a premature stop codon. Using this method, Freddi et al. (2000) screened a 4-generation family with Stickler syndrome and identified a protein-truncating mutation that was present in all affected individuals. Targeted sequencing identified the mutation as a G-to-A transition at the +1 position of the 5-prime splice donor site of intron 25. The mutation led to the activation of a cryptic splice site 8 bp upstream, causing aberrant mRNA splicing and a translational frameshift that introduced a premature stop codon. Mutant mRNA was undetectable without cycloheximide protection, demonstrating that the mutant mRNA was subjected to nonsense-mediated mRNA decay.