Description
Variant summary: PYGM c.1094C>T (p.Ala365Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5 donor site. One predicts the variant strengthens a cryptic 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00071 in 224920 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00071 vs 0.0035), allowing no conclusion about variant significance. In a conservative assessment of the literature, c.1094C>T has been reported in compound heterozygosity in individuals affected with Glycogen Storage Disease, Type V (example, Vieitez_2011, Rubio_2007, Bruno_2006, Lucia_2012, Inal-Gultekin_2017, Santalla_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16786513, 25741863, 28967462, 22250184, 17221871, 29143597, 21802952). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5), likely pathogenic (n=5) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely 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 |
