Variant: NM_000152.5(GAA):c.1735G>A (p.Glu579Lys)

CA294895841

495664 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 751727f5-33d5-4e67-a898-c4ef9dba3fcc

Approved on: 2022-12-06

Published on: 2022-12-20

HGVS expressions

NM_000152.5:c.1735G>A
NM_000152.5(GAA):c.1735G>A (p.Glu579Lys)
NC_000017.11:g.80112081G>A
CM000679.2:g.80112081G>A
NC_000017.10:g.78085880G>A
CM000679.1:g.78085880G>A
NC_000017.9:g.75700475G>A
NG_009822.1:g.15526G>A
ENST00000302262.8:c.1735G>A
ENST00000302262.7:c.1735G>A
ENST00000390015.7:c.1735G>A
ENST00000572080.1:n.123G>A
ENST00000572803.1:n.349G>A
NM_000152.3:c.1735G>A
NM_001079803.1:c.1735G>A
NM_001079804.1:c.1735G>A
NM_000152.4:c.1735G>A
NM_001079803.2:c.1735G>A
NM_001079804.2:c.1735G>A
NM_001079803.3:c.1735G>A
NM_001079804.3:c.1735G>A

Pathogenic

• Met criteria codes: PS3_Moderate PM2_Supporting PP4_Moderate PM3_Strong PP3

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.:c.1735G>A variant in GAA is a missense variant predicted to result in the substitution of glutamate by lysine at amino acid 579 (p.Glu579Lys). Five patients with a diagnosis of Pompe disease and the variant have been reported, three with documented laboratory values showing deficiency of GAA activity (PMID: 21676566, 23601496, 29124014, 34357340), one with reported features consistent with infantile-onset Pompe disease (PMID: 24269976), and another reported to have Pompe disease (PMID: 14695532) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, all phase unknown, including c.-32-13T>G (PMID: 34357340) (0.5 points), c.525delT (PMID: 14695532) (0.5 points), c.2237G>A (p.Trp746Ter) (PMID: 24269976) (0.5 points), and c.655G>A (p.Gly219Arg) (PMIDs: 23601496, 31086307,31193175) (0.5 points). Total 2 points (PM3_Strong). Another patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg) (PMIDs: 21676566, 29124014) The allelic data from this patient will be used in the classification of p.Ser619Arg and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/129092) in the European Non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% GAA activity in cells and <2% in medium, evidence of abnormal synthesis and processing on Western blot, and did not localize to the lysosomes (PMID: 14695532, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.878 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: 495664). In summary this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the Clingen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on December 6, 2022)

Met criteria codes

• PS3_Moderate: When expressed in COS cells, this variant had <5% GAA activity in cells and <2% in medium, evidence of abnormal synthesis and processing on Western blot, and did not localize to the lysosomes (PMID: 14695532, 19862843) (PS3_Moderate).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/129092) in the European Non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion.
• PP4_Moderate: Five patients with a diagnosis of Pompe disease and the variant have been reported, three with documented laboratory values showing deficiency of GAA activity (PMID: 21676566, 23601496, 29124014, 34357340) (2 points each, meeting PP4_Moderate), one with reported features consistent with infantile-onset Pompe disease (PMID: 24269976) (1 point, PP4), in addition to another reported patient with insufficient detail to apply PP4 (PMID: 14695532).
• PM3_Strong: Four patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, all phase unknown, including c.-32-13T>G (PMID: 34357340) (0.5 points), c.525delT (PMID: 14695532) (0.5 points), c.2237G>A (p.Trp746Ter) (PMID: 24269976) (0.5 points), and c.655G>A (p.Gly219Arg) (PMID: 23601496, 31086307, 31193175) (0.5 points). Total 2 points (PM3_Strong). Another patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg) (PMIDs: 21676566, 29124014) The allelic data from this patient will be used in the classification of p.Ser619Arg and is not included here to avoid circular logic.
• PP3: The computational predictor REVEL gives a score of 0.878 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). SpliceAI predicts no impact on splicing.