Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000306541 | SCV002817436 | likely pathogenic | Glycogen storage disease, type II | 2022-09-20 | reviewed by expert panel | curation | The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID: 18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID: 21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) variant meets the criteria to be classified as likely pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) |
Eurofins Ntd Llc |
RCV000725236 | SCV000335210 | pathogenic | not provided | 2015-09-15 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000306541 | SCV000486956 | likely pathogenic | Glycogen storage disease, type II | 2016-09-13 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000306541 | SCV001212310 | pathogenic | Glycogen storage disease, type II | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 375 of the GAA protein (p.Arg375Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pompe disease (PMID: 18429042, 22990675, 24158270, 29422078). ClinVar contains an entry for this variant (Variation ID: 283230). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 18429042). This variant disrupts the p.Arg375 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21757382), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Broad Center for Mendelian Genomics, |
RCV000306541 | SCV001422909 | likely pathogenic | Glycogen storage disease, type II | 2020-01-22 | criteria provided, single submitter | curation | The p.Arg375Leu variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22081099, 24158270, 25103075, 25396301, 18429042) and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 283230). This variant has been identified in 0.002% (2/111942) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142752477). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with a GAA-deficient human fibroblast cell line provide some evidence that the p.Arg375Leu variant may impact GAA production and activity (PMID: 18429042). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with 2 pathogenic variants curated by our study in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Arg375Leu variant is pathogenic (PMID: 22081099, 24158270, 25103075, 25396301, 18429042). The phenotype of 3 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity in muscle tissue <10% of normal, consistent with disease (PMID: 24158270, 22081099). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Supporting, PM2, PP3, PP4 (Richards 2015). |
Revvity Omics, |
RCV000725236 | SCV002021203 | pathogenic | not provided | 2022-05-11 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000306541 | SCV002598559 | pathogenic | Glycogen storage disease, type II | 2022-09-19 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.1124G>T (p.Arg375Leu) 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 allele was found at a frequency of 8e-06 in 248456 control chromosomes. c.1124G>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Parenti_2007). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Fulgent Genetics, |
RCV000306541 | SCV002784081 | likely pathogenic | Glycogen storage disease, type II | 2021-08-11 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000306541 | SCV004197865 | pathogenic | Glycogen storage disease, type II | 2023-03-03 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV000306541 | SCV002091991 | pathogenic | Glycogen storage disease, type II | 2020-09-23 | no assertion criteria provided | clinical testing |