ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1942G>A (p.Gly648Ser) (rs536906561)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000169262 SCV001371752 pathogenic Glycogen storage disease, type II 2020-04-21 reviewed by expert panel curation This variant, c.1942G>A (p.Gly648Ser), has been reported in at least six patients with Pompe disease with residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4 (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962). Of these patients, one is compound heterozygous for the variant and c.-32-13T>G (PMID 9535769), one is heterozygous for the variant and c.2646+2T>A (PMID 29422078), and two are homozygous for the variant (PMIDs 26497565, 30214072), meeting PM3. Another patient is compound heterozygous for the variant and c.1076-22T>G (PMID 17573812), however, this in trans data will be used in the assessment of c.1076-22T>G and will not be included here in order to avoid a circular argument. Of note, there is a high incidence of this variant in the Maroon population of French Guiana (PMID 29637184). Of 12 patients with “enzymatically confirmed” infantile-onset Pompe disease, 9 were compound heterozygous for p.Gly648Ser and p.Arg854Ter. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00034 in the South Asian population, meeting PM2. When this variant was expressed in SV40_immortalized GAA deficient fibroblasts, the GAA activity was "negligible" (PMID 9535769), meeting PS3. The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function, meeting PP3. Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID 188902, 2 star review status) with one submitter classifying the variant as pathogenic and another as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PP3, PP4.
Counsyl RCV000169262 SCV000220552 likely pathogenic Glycogen storage disease, type II 2014-07-24 criteria provided, single submitter literature only
Invitae RCV000169262 SCV000626535 pathogenic Glycogen storage disease, type II 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 648 of the GAA protein (p.Gly648Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs536906561, ExAC 0.05%). This variant has been reported in combination with another GAA variant in individuals affected with glycogen storage disease type II (Pompe disease) (PMID: 9535769, 17643989, 26575883), including the finding of this variant on the opposite chromosome (in trans) from a pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 188902). Experimental studies have shown that this missense change causes a severe reduction in GAA enzyme activity (PMID: 9535769, 19862843). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Gly648Asp) has been reported in an individual affected with Pompe disease (PMID: 23146291, 22644586). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169262 SCV001361272 pathogenic Glycogen storage disease, type II 2019-01-07 criteria provided, single submitter clinical testing Variant summary: GAA c.1942G>A (p.Gly648Ser) results in a non-conservative amino acid change in the Glycoside hydrolase superfamily (IPR017853) 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 5.5e-05 in 237998 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (5.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.1942G>A has been reported in the literature in multiple individuals affected with adult onset and infantile onset Glycogen Storage Disease, Type 2 (Pompe Disease)(Huie_1998, Elenga_2018). A patient diagnosed with adult onset Pompe Disease was observed to have <10% enzyme activity in vivo. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000169262 SCV001423120 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gly648Ser variant in GAA has been reported in 15 individuals with Glycogen Storage Disease II (PMID: 29637184, 17573812, 26497565, 17643989, 25455803, 9535769), and has also been reported pathogenic by Invitae and likely pathogenic by Counsyl in ClinVar (Variation ID: 188902). This variant has been identified in 0.034% (10/29720) of South Asian chromosomes in gnomAD chromosomes in gnomAD by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs536906561). 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 provide some evidence that the p.Gly648Ser variant may impact GAA activity (PMID: 9535769). 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 the homozygous state and in combination with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly648Ser variant is pathogenic (PMID: 29637184, 17573812, 26497565, 17643989, 25455803, 9535769). Individuals with this variant in the homozygous and heterozygous state and a phenotype highly specific for disease based on assays of GAA activity in relevant tissue (PMID: 29637184, 17573812, 26497565, 9535769). One additional likely pathogenic variant resulting in a different amino acid change at the same position, p.Gly648Asp, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22644586). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PM5_Supporting, PP3, PP4 (Richards 2015).

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