Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001806841 | SCV002051415 | likely pathogenic | Glycogen storage disease, type II | 2021-12-29 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.1748C>T (p.Ser583Phe) 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 251184 control chromosomes (gnomAD). c.1748C>T has been reported in the literature in at least two individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Kroos_2008, Bali_2011, Harlaar_2019). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated 0.1-1% activity in fibroblasts derived from a compound heterozygous patient (Bali_2011), in addition the variant protein showed absent activity in an in vitro expression system (Kroos_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV001806841 | SCV002109923 | pathogenic | Glycogen storage disease, type II | 2022-10-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 583 of the GAA protein (p.Ser583Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 31619483). ClinVar contains an entry for this variant (Variation ID: 1331497). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 18425781). |