Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001585686 | SCV004227912 | uncertain significance | Glycogen storage disease, type II | 2023-12-19 | reviewed by expert panel | curation | The NM_000152.5:c.12105G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 702 (p.Arg702Pro). It has been reported in one individual in national mutation database for the country of Oman (PMID: 26594346). This individual was reported to be compound heterozygous for this variant and a pathogenic variant, phase unknown (PM3). However, no clinical details were provided and thus points can not be applied for PP4. The highest population minor allele frequency in gnomAD v4.0.0 is 0.0000009 (1/1105906 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 593593, 1-star review status) with three submitters classifying the variant likely pathogenic (2) and uncertain significance (1). Due to insufficient evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): (PM3_supporting, PM2_supporting, PP3). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023). |
| Eurofins Ntd Llc |
RCV000728685 | SCV000856289 | likely pathogenic | not provided | 2017-08-16 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193012 | SCV001361536 | uncertain significance | not specified | 2019-07-01 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.2105G>C (p.Arg702Pro) affects a highly conserved nucleotide and 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. The variant was absent in 222484 control chromosomes (gnomAD). c.2105G>C has been reported in the literature in compound heterozygosity with a pathogenic GAA variant in an individual affected with Glycogen Storage Disease Type 2 (Pompe Disease), but limited information was provided on the case (Rajab_2015). These data therefore do not allow unequivocal conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a variant affecting the same nucleotide but leading to a different missense change (c.2105G>A/p.Arg702His) has been classified by our laboratory as pathogenic. In addition, other variants affecting the same codon have been reported in affected individuals (c.2104C>T (p.Arg702Cys), c.2105G>T (p.Arg702Leu); in ClinVar and HGMD) suggesting a functional importance for this location. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Genome- |
RCV001585686 | SCV001810642 | likely pathogenic | Glycogen storage disease, type II | 2021-07-22 | criteria provided, single submitter | clinical testing |