chr17-80112655-G-A
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM3PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1832G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 611 (p.Gly611Asp). Four patients with a diagnosis of Pompe disease and this variant have been reported including two with documented features of infantile onset Pompe disease and laboratory values showing deficient GAA activity <1% in skin fibroblasts (PMID:22252923) or in the affected range in dried blood spot assay (PMID:25681614), and another reported with features consistent with infantile onset Pompe disease and deficient GAA activity but the laboratory value was not provided (PMID:24269976). Finally, a patient with deficient GAA activity (level not known) was identified in clinical laboratory data (PP4_Moderate). Of the reported patients, three are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.2501_2502delCA, (pathogenic, presumed in trans, clinical laboratory data), c.1848dupC (clinical laboratory data) (pathogenic, phase unknown), and c.1843G>A (p.Gly615Arg) (PMID:24269976) (likely pathogenic, phase unknown), and one patient is homozygous (PMID:25681614). Another patient is compound heterozygous for the variant and c.1570A>T (p.Asn524Tyr). However, the allelic data from this patient with be used in the assessment of p.Asn524Tyr and is not included here to avoid circular logic. (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.821 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1831G>A, p.Gly611Ser) (ClinVar variation ID: 935199) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP. However, the data from c.1832 (p.Gly611Asp) was used in the classification of p.Gly611Ser, and therefore the data is not ncluded here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 371226, 1 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this 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 (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041897/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
Publications
- glycogen storage disease IIInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
- glycogen storage disease due to acid maltase deficiency, infantile onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- glycogen storage disease due to acid maltase deficiency, late-onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00 AC: 0AN: 245780 AF XY: 0.00
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 611 of the GAA protein (p.Gly611Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease and reduced GAA enzymatic activity (PMID: 22252923, 24269976, 25681614; internal data). ClinVar contains an entry for this variant (Variation ID: 371226). 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%. For these reasons, this variant has been classified as Pathogenic. -
The p.Gly611Asp variant in GAA has been reported in 4 individuals (including 1 Chinese individual) with Glycogen Storage Disease II (PMID: 25681614, 22252923, 24269976), and has also been reported as a likely pathogenic variant by Counsyl and Invitae in ClinVar (Variation ID: 371226). This variant was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Gly611Asp variant is pathogenic (PMID: 25681614). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA enzyme in a dried blood spot, consistent with disease (PMID: 25681614). In summary, the clinical significance of the p.Gly611Asp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_Supporting, PP4 (Richards 2015). -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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The NM_000152.5:c.1832G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 611 (p.Gly611Asp). Four patients with a diagnosis of Pompe disease and this variant have been reported including two with documented features of infantile onset Pompe disease and laboratory values showing deficient GAA activity <1% in skin fibroblasts (PMID: 22252923) or in the affected range in dried blood spot assay (PMID: 25681614), and another reported with features consistent with infantile onset Pompe disease and deficient GAA activity but the laboratory value was not provided (PMID: 24269976). Finally, a patient with deficient GAA activity (level not known) was identified in clinical laboratory data (PP4_Moderate). Of the reported patients, three are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.2501_2502delCA, (pathogenic, presumed in trans, clinical laboratory data), c.1848dupC (clinical laboratory data) (pathogenic, phase unknown), and c.1843G>A (p.Gly615Arg) (PMID: 24269976) (likely pathogenic, phase unknown), and one patient is homozygous (PMID: 25681614). Another patient is compound heterozygous for the variant and c.1570A>T (p.Asn524Tyr). However, the allelic data from this patient with be used in the assessment of p.Asn524Tyr and is not included here to avoid circular logic. (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.821 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1831G>A, p.Gly611Ser) (ClinVar variation ID: 935199) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP. However, the data from c.1832 (p.Gly611Asp) was used in the classification of p.Gly611Ser, and therefore the data is not ncluded here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 371226, 1 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this 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 (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at