Description
Variant summary: GNE c.1505-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 251248 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.00014 vs 0.0011), allowing no conclusion about variant significance. c.1505-4G>A has been reported in the literature in at-least one Japanese individual with clinically and pathologically confirmed (prominent rimmed vacuoles in muscle biopsy) GNE myopathy (example, Nakamura_2017), as a non-informative genotype in another Japanese individual with GNE myopathy (example, Cho_2013) and has been cited by others (Celeste_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
