Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002260943 | SCV002540665 | likely pathogenic | Glycogen storage disease, type II | 2022-06-30 | reviewed by expert panel | curation | The NM_000152.5(GAA):c.2456G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 819 (p.Arg819Pro). This variant has been detected in at least 6 individuals with Pompe disease (PMID: 22644586, 22252923, 30214072) with deficient GAA activity. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and one was homozygous for the variant (PMID: 30214072, internal lab data), meeting PP4_Moderate and PM3. It is absent in gnomAD, meeting PM2. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PP4_Moderate, PM3, PS3_Moderate, PP3, PM2_Supporting, and PM5_Supporting. |
| Revvity Omics, |
RCV003491062 | SCV004238202 | likely pathogenic | not provided | 2023-07-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002260943 | SCV005076700 | pathogenic | Glycogen storage disease, type II | 2024-04-11 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.2456G>C (p.Arg819Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 31, C-terminal domain (IPR048395) of 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 242628 control chromosomes. c.2456G>C has been reported in the literature in several individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; e.g. Bali_2012, Kazi_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Kroos_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22252923, 22644586, 30214072). ClinVar contains an entry for this variant (Variation ID: 1693550). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV002260943 | SCV005653252 | likely pathogenic | Glycogen storage disease, type II | 2024-01-05 | criteria provided, single submitter | clinical testing |