Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000553278 | SCV002817439 | uncertain significance | Glycogen storage disease, type II | 2023-01-02 | reviewed by expert panel | curation | The NM_000152.5:c.265C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 89 (p.Arg89Cys). At least 1 proband with this variant had documented GAA deficiency with activity in the affected range in dried blood spot was reported (clinical laboratory data). The patient is heterozygous for the pseudodeficiency variant(s) c.271G>A (p.Asp91Asn) and therefore the GAA activity cannot be used for PP4. The proband is compound heterozygous for the variant and a variant classified as Pathogenic by the ClinGen LSD VCEP, c.307T>G (p.Cys103Gly); the variants are confirmed in trans by parental testing. However, the phase of the pseudodeficiency variant is unknown so PM3 was not applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.001898 (58/30556 alleles) in the South Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). One other missense variant, c.266G>A (p.Arg89His) (ClinVar Variation ID: 283219) has been reported in patients with Pompe disease (PMID: 28196920, 28600779, 25626711, 33202836). However, this variant has been classified as a variant of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 456412; 1 star review status) with one submitter classifying the variant as Likely Pathogenic and 5 as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. (Classification approved by the ClinGen LSD VCEP on December 20, 2022) |
Labcorp Genetics |
RCV000553278 | SCV000626590 | likely pathogenic | Glycogen storage disease, type II | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the GAA protein (p.Arg89Cys). This variant is present in population databases (rs534192892, gnomAD 0.2%). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (internal data). ClinVar contains an entry for this variant (Variation ID: 456412). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg89 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25626711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Fulgent Genetics, |
RCV000553278 | SCV000895136 | uncertain significance | Glycogen storage disease, type II | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001557806 | SCV001779639 | uncertain significance | not provided | 2019-11-05 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
Genome- |
RCV000553278 | SCV002027207 | uncertain significance | Glycogen storage disease, type II | 2021-09-05 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV001821499 | SCV002072179 | uncertain significance | not specified | 2017-11-15 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV001557806 | SCV003828484 | uncertain significance | not provided | 2023-12-04 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001821499 | SCV005727291 | uncertain significance | not specified | 2024-11-03 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.265C>T (p.Arg89Cys) results in a non-conservative amino acid change located in the P-type trefoil domain of 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 0.00025 in 248200 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00025 vs 0.0042), allowing no conclusion about variant significance. c.265C>T has been reported in the literature in individuals affected with a positive newborn screening result for GAA-related disease (example: Sniderman_2023, Tang_2020, Internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37087815, 33073007, 33560568, No_PMID). ClinVar contains an entry for this variant (Variation ID: 456412). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Natera, |
RCV000553278 | SCV002091900 | uncertain significance | Glycogen storage disease, type II | 2020-01-23 | no assertion criteria provided | clinical testing |