NM_000152.5:c.1927G>A
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_ModeratePP3PS3_ModeratePM2_SupportingPM3
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1927G>A variant in GAA is predicted to result in the substitution of glycine by arginine at amino acid 643 (p.Gly643Arg). Numerous individuals have been reported with this variant and specific features of Pompe disease including GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay; patients with specific features of infantile onset Pompe disease (including cardiac features and hypotonia_, and on enzyme replacement therapy (PMIDs: 8401535, 17723315, 23430912, 23609349 24158270, 25783438, 26349193, 26497565) (PP4_Moderate). The variant has been reported in patients with Pompe disease who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. In these cases, the second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (at least 10 cases; maximum 2 x 0.5 points; PMID:16917947, 18607768, 20308911, 23609349, 24158270, 25396301, 25783438, 27862019, 30155607), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1 (2 cases, 2 x 0.5 points) (PMID:18429042, 23430912), c.1064T>C (p.Leu355Pro) (ClinVar Variation ID: 284093, SCV001371747.2) (0.5 points, PMID:18429042), c.236_246del (p.Pro79fsTer) (ClinVar Variation ID: 371302, SCV001443298.1 (0.5 points, PMID:19588081), and c.2662G>T (p.Glu888Ter) (ClinVar Variation ID: 578595, SCV001371767.1 (0.5 points, PMID:28394184). First cousins have been reported who are compound heterozygous for the variant (inherited from their heterozygous mothers who are sisters) and another pathogenic variant in GAA variant; c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) in one individual, and "deletion of exon 18" in the other individual (PMID:26349193). In each case, the second variant was shown to be inherited from the father. Although the genotypes are different, only one case will be counted from this family, as they are related (1 point, pathogenic variant confirmed in trans). At least 2 cases are homozygous for the variant (max 2 x 0.5 points, PMID:18429042, 24002816, 26497565, 30023291). Additional cases are compound heterozygous for the variant and either c.2040G>A (PMID:17723315) or c.2173C>T (p.Arg725Trp) (PMID:8401535). The in trans data for these patients was used in the classification of the other variant as is not included here to avoid circular logic. Finally, the variant is reported in other cases and publications without sufficient evidence to apply PM3 (PMID:9521422, 17915575, 19862843, 22081099, 29880332) Additional cases may be available in the literature but PM3 is already applied at very strong (>5 points) (PM3_VeryStrong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003667 (4/109080 alleles) in the European non-Finnish population. In gnomAD v4.1, the MAF is 0.00003224 (40/1178798 alleles) in the European non-Finnish population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The activity of this variant, when expressed in COS cells, has been analyzed in several studies (PMIDs: 8401535, 9521422, 19862843) and varies from <2%-6% with 4MUG and ~3% wild type activity in cells with glycogen. Pulse chase analysis showed that the protein is abnormally processed, with most of the protein remaining as precursor (PMID:8401535) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 4023). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116596/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000248 AC: 6AN: 242074Hom.: 0 AF XY: 0.0000228 AC XY: 3AN XY: 131738
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1458226Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22AN XY: 725064
GnomAD4 genome
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:11
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Variant summary: GAA c.1927G>A (p.Gly643Arg) 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 2.5e-05 in 242074 control chromosomes. c.1927G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; eg. Hermans_1993, Laforet_2000, McCready_2007, Oba-Shinjo_2009, Pittis_2008). Experimental evidence has shown the variant to result in impairment of intracellular transport and maturation of the protein, resulting in severe enzyme deficiency (Hermans_1993) Four 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
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The c.1927G>A (p.Gly643Arg) in compound heterocigosity with c.-32-13T>G GAA variant has been reported in our laboratory in a 15-year-old boy with diagnosis of Pompe disease (onset 13 years old) with no family history and alpha-1,4-glucosidase lysosomal enzyme activity study: 0,47 µmol/L/h (ref. values: 0.75-5.0). Pompe Variant Database describes this phenotype in seven patients, with age of onset and variable phenoty. It has been previously reported in patients with Pompe disease both in the homozygous and heterozygous state (PMID: 30023291, 25052852, 17056254, 25783438, 30155607, 26349193, 11071489, 20559845, 26497565, 19588081, 18607768, 19862843, 18429042, 17723315, 16917947, 9521422, 8401535). This variant is present in population databases (gnomAD allele frequency 0.00002476). ClinVar contains an entry for this variant (Variation ID: 4023) with no conflicts. Experimental evidence has shown the variant to result in impairment of intracellular transport and maturation of the protein, resulting in severe enzyme deficiency (PMID: 8401535). In summary, c.1927G>A (p.Gly643Arg) GAA variant meets our criteria to be classified as pathogenic for Pompe disease in an autosomal recessive manner based upon functional evidence and its identification in numerous affected individuals. -
A homozygous missense variation in exon 14 of the GAA gene that results in the amino acid substitution of Arginine for Glycine at codon 643 was detected. The observed variant c.1927G>A (p.Gly643Arg) has not been reported in the 1000 genomes and has a MAF of 0.002% in the gnomAD databases. The in silico prediction of the variant is by DANN, LRT, MutationTaster, SIFT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
The NM_000152.5:c.1927G>A variant in GAA is predicted to result in the substitution of glycine by arginine at amino acid 643 (p.Gly643Arg). Numerous individuals have been reported with this variant and specific features of Pompe disease including GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay; patients with specific features of infantile onset Pompe disease (including cardiac features and hypotonia_, and on enzyme replacement therapy (PMIDs: 8401535, 17723315, 23430912, 23609349 24158270, 25783438, 26349193, 26497565) (PP4_Moderate). The variant has been reported in patients with Pompe disease who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. In these cases, the second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (at least 10 cases; maximum 2 x 0.5 points; PMID: 16917947, 18607768, 20308911, 23609349, 24158270, 25396301, 25783438, 27862019, 30155607), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1 (2 cases, 2 x 0.5 points) (PMID: 18429042, 23430912), c.1064T>C (p.Leu355Pro) (ClinVar Variation ID: 284093, SCV001371747.2) (0.5 points, PMID: 18429042), c.236_246del (p.Pro79fsTer) (ClinVar Variation ID: 371302, SCV001443298.1 (0.5 points, PMID: 19588081), and c.2662G>T (p.Glu888Ter) (ClinVar Variation ID: 578595, SCV001371767.1 (0.5 points, PMID: 28394184). First cousins have been reported who are compound heterozygous for the variant (inherited from their heterozygous mothers who are sisters) and another pathogenic variant in GAA variant; c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) in one individual, and "deletion of exon 18" in the other individual (PMID: 26349193). In each case, the second variant was shown to be inherited from the father. Although the genotypes are different, only one case will be counted from this family, as they are related (1 point, pathogenic variant confirmed in trans). At least 2 cases are homozygous for the variant (max 2 x 0.5 points, PMID: 18429042, 24002816, 26497565, 30023291). Additional cases are compound heterozygous for the variant and either c.2040G>A (PMID: 17723315) or c.2173C>T (p.Arg725Trp) (PMID: 8401535). The in trans data for these patients was used in the classification of the other variant as is not included here to avoid circular logic. Finally, the variant is reported in other cases and publications without sufficient evidence to apply PM3 (PMID:9521422, 17915575, 19862843, 22081099, 29880332) Additional cases may be available in the literature but PM3 is already applied at very strong (>5 points) (PM3_VeryStrong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003667 (4/109080 alleles) in the European non-Finnish population. In gnomAD v4.1, the MAF is 0.00003224 (40/1178798 alleles) in the European non-Finnish population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The activity of this variant, when expressed in COS cells, has been analyzed in several studies (PMIDs: 8401535, 9521422, 19862843) and varies from <2%-6% with 4MUG and ~3% wild type activity in cells with glycogen. Pulse chase analysis showed that the protein is abnormally processed, with most of the protein remaining as precursor (PMID: 8401535) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 4023). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen -
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This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 643 of the GAA protein (p.Gly643Arg). This variant is present in population databases (rs28937909, gnomAD 0.004%). This missense change has been observed in individual(s) with Pompe disease (PMID: 8401535, 18607768, 24158270). ClinVar contains an entry for this variant (Variation ID: 4023). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 8401535). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
The p.Gly643Arg variant in GAA has been reported in the homozygous and heterozygous state in at least 31 individuals (including 8 Italian, 7 French, 3 Brazilian, 1 German, 1 from the UK, 1 Argentinian, 1 Canadian, and 1 Saudi Arabian individuals) with Glycogen Storage Disease II (PMID: 30023291, 25052852, 17056254, 25783438, 30155607, 26349193, 11071489, 20559845, 26497565, 19588081, 18607768, 19862843, 18429042, 17723315, 16917947, 9521422, 8401535), and has also been reported pathogenic by Invitae, Counsyl, Blueprint Genetics, and OMIM in ClinVar (Variation ID: 4023). This variant has been identified in 0.004% (4/109080) of European (non-Finnish) chromosomes, 0.003% (1/29618) of South Asian chromosomes, and 0.003% (1/33956) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28937909). 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 COS cells transfected with the variant and structural analysis provide some evidence that the p.Gly643Arg variant may impact the GAA active site, GAA processing, and GAA activity (PMID: 19862843, 9521422, 8401535, 25103075). 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.Gly643Arg variant is pathogenic (PMID: 24158270, 17056254, 17723315, 11071489, 26497565). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues (PMID: 24158270, 17056254, 17723315, 11071489, 26497565). 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 with COS cells transfected with this variant, and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP3, PP4 (Richards 2015). -
not provided Pathogenic:3
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GAA: PM3:Very Strong, PM2, PP3 -
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GLYCOGEN STORAGE DISEASE II, ADULT FORM Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at