Variant: NM_000152.5(GAA):c.266G>A (p.Arg89His)

CA8814833

283219 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: d7536a64-be9f-410a-a04b-2eeea00d3e38

Approved on: 2024-04-16

Published on: 2024-04-17

HGVS expressions

NM_000152.5:c.266G>A
NM_000152.5(GAA):c.266G>A (p.Arg89His)
NC_000017.11:g.80104852G>A
CM000679.2:g.80104852G>A
NC_000017.10:g.78078651G>A
CM000679.1:g.78078651G>A
NC_000017.9:g.75693246G>A
NG_009822.1:g.8297G>A
ENST00000570803.6:c.266G>A
ENST00000572080.2:c.266G>A
ENST00000577106.6:c.266G>A
ENST00000302262.8:c.266G>A
ENST00000302262.7:c.266G>A
ENST00000390015.7:c.266G>A
ENST00000570803.5:c.266G>A
ENST00000577106.5:c.266G>A
NM_000152.3:c.266G>A
NM_001079803.1:c.266G>A
NM_001079804.1:c.266G>A
NM_000152.4:c.266G>A
NM_001079803.2:c.266G>A
NM_001079804.2:c.266G>A
NM_001079803.3:c.266G>A
NM_001079804.3:c.266G>A

Uncertain Significance

• Met criteria codes: BS3_Supporting PP3 PM3 PP4_Moderate PM2_Supporting

• Not Met criteria codes: PM5

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.266G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 89 (p.Arg89His). Two individuals with this variant have been reported to exhibit clinical symptoms of infantile onset Pompe disease, one of them on enzyme replacement therapy (PMID: 22644586 25626711) (PP4_Moderate). One of them is homozygous for c.[266G>A, 546+45G>C] (PMID: 22644586), and the other is compound heterozygous for c.266G>A and c.104T>C (p.Phe35Ser) (PMID: 25626711). The clinical significance of c.[266G>A, 546+45G>C] and c.104T>C (p.Phe35Ser) is unknown. The variant was also found in compound heterozygosity with c.2237G>C (p.Trp746Ser) (LP based on classification by the ClinGen Lysosomal Diseases VCEP) by exome sequencing in a proband, confirmed in trans; three siblings have the same genotype. Three of the siblings have GAA activity consistent with late onset disease, and GAA activity was slightly above this range in the remaining sibling. However, none of them have developed clinical symptoms of Pompe disease yet (see ClinVar Variation ID: 283219; SCV003927052.1). Individuals identified by newborn screen, and so far clinically asymptomatic, have the genotype c.-32-13T>G/c.266G>A; c.1377C>G (PMID: 33202836); or are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.1655T>C (p.Leu552Pro) (PMID: 33202836) or c.525delT (PMID: 28196920). Another individual, with dual molecular diagnoses of GSD 1, and Pompe is homozygous for c.266G>A (p.Arg89His) but no clinical details are available (PMID: 28600779). Therefore, without reports of any symptomatic individuals who have this variant in trans with a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.001168 in the Ashkenazi Jewish population (12/10272; no homozygotes). The highest population minor allele frequency in a continental population in gnomAD v2.1.1. is 0.00016 (5/30550) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.819 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). When expressed in COS cells, this variant was classified as Class E ("presumably nonpathogenic") by Kroos et al, 2012 (PMID:22644586). This includes 43.5% GAA activity in cells and 20% in medium, and is normally synthesized (though less than normal) and processed on Western blot (BS3_Supporting). Three other missense variants at the same position have been reported - c.265C>T (p.Arg89Cys) (VUS based on classification by the ClinGen LD VCEP; ClinVar Variation ID: 456412, SCV002817439.1), c.265C>A (p.Arg89Ser) (ClinVar Variation ID: 1989151), and c.266G>T (p.Arg89Leu) (ClinVar Variation ID: 2754338) (not yet classified by the ClinGen LD VCEP).There is a ClinVar entry for this variant (Variation ID: 283219). In summary, this variant meets the criteria to be classified as a Variant of Unknown Significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PP3, PM2_Supporting, BS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 16, 2024).

Met criteria codes

• BS3_Supporting: When expressed in COS cells, this variant was classified as Class E ("presumably nonpathogenic") by Kroos et al, 2012 (PMID:22644586). This includes 43.5% GAA activity in cells and 20% in medium, and is normally synthesized (though less than normal) and processed on Western blot. This meets the ClinGen Lysosomal VCEP specifications for BS3_Supporting.
• PP3: The computational predictor REVEL gives a score of 0.819 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).
• PM3: Two individuals with this variant have been reported to exhibit clinical symptoms of infantile onset Pompe disease. One of them is homozygous for c.[266G>A, 546+45G>C] (PMID: 22644586), and the other is compound heterozygous for c.266G>A and c.104T>C (p.Phe35Ser) (PMID: 25626711). The clinical significance of c.[266G>A, 546+45G>C] and c.104T>C (p.Phe35Ser) is unknown. Therefore, no points were given for PM3. The variant was also found in compound heterozygosity with c.2237G>C (p.Trp746Ser) (LP based on classification by the ClinGen Lysosomal Diseases VCEP) by exome sequencing in a proband, confirmed in trans; three siblings have the same genotype. Three of the siblings have GAA activity consistent with late onset disease, and GAA activity was slightly above this range in the remaining sibling. However, none of them have developed clinical symptoms of Pompe disease yet (see ClinVar Variation ID: 283219; SCV003927052.1). Individuals identified by newborn screen, and so far clinically asymptomatic, have the genotype c.-32-13T>G/c.266G>A; c.1377C>G (PMID: 33202836); or are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.1655T>C (p.Leu552Pro) (PMID: 33202836) or c.525delT (PMID: 28196920). Another individual, with dual molecular diagnoses of GSD 1, and Pompe is homozygous for c.266G>A (p.Arg89His) but no clinical details are available (PMID: 28600779). Therefore, without reports of any symptomatic individuals who have this variant in trans with a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, PM3 is not met at the current time.
• PP4_Moderate: Two probands with this variant have been reported with a diagnosis of infantile onset Pompe disease, one of them on enzyme replacement therapy (PMID: 25626711, PMID: 22644586). Otherwise, the variant has been identified in patients without symptoms of Pompe disease. This includes individuals with suspected late onset disease identified by newborn screen ( (PMID: 28196920, 33073007, 33202836) in addition to four affected siblings identified with two GAA variants by exome sequencing; three of the siblings had GAA activity "within the range for LOPD patients" and activity was "slightly above the upper limit" for the remaining sibling (ClinVar Variation ID 283219, SCV003927052.1). Finally, another patient was found by molecular diagnosis only with no further information (PMID: 28600779).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.001168 in the Ashkenazi Jewish population (12/10272; no homozygotes). The highest population minor allele frequency in a continental population in gnomAD v2.1.1. is 0.00016 (5/30550) in the South Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion.

Not Met criteria codes

• PM5: Three other missense variants at the same position have been reported - c.265C>T (p.Arg89Cys) (VUS based on classification by the ClinGen LD VCEP; ClinVar Variation ID: 456412, SCV002817439.1), c.265C>A (p.Arg89Ser) (ClinVar Variation ID: 1989151), and c.266G>T (p.Arg89Leu) (ClinVar Variation ID: 2754338) (not yet classified by the ClinGen LD VCEP).