Variant: NM_000152.5(GAA):c.671G>A (p.Arg224Gln)

CA8814958

664582 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 294201df-508f-4188-a0a6-9c7f1bc8ea0b

HGVS expressions

NM_000152.5:c.671G>A
NM_000152.5(GAA):c.671G>A (p.Arg224Gln)
NC_000017.11:g.80105873G>A
CM000679.2:g.80105873G>A
NC_000017.10:g.78079672G>A
CM000679.1:g.78079672G>A
NC_000017.9:g.75694267G>A
NG_009822.1:g.9318G>A
ENST00000302262.8:c.671G>A
ENST00000302262.7:c.671G>A
ENST00000390015.7:c.671G>A
ENST00000570803.5:c.671G>A
NM_000152.3:c.671G>A
NM_001079803.1:c.671G>A
NM_001079804.1:c.671G>A
NM_000152.4:c.671G>A
NM_001079803.2:c.671G>A
NM_001079804.2:c.671G>A
NM_001079803.3:c.671G>A
NM_001079804.3:c.671G>A

Likely Pathogenic

• Met criteria codes: PP3 PM5 PM3 PP4_Moderate PM2_Supporting PS3_Moderate

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.671G>A variant in GAA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 224 (p.Arg224Gln). This variant has been reported in one individual with documented GAA deficiency (PMID: 23000108), meeting criteria for PP4_moderate. This individual is compound heterozygous for the variant and a pathogenic variant based on the ClinGen LSD VCEP's specifications. It has also been reported in two individuals described as having late-onset Pompe disease diagnosed after positive newborn screening in Taiwan, though no phenotype is reported. One individual is compound heterozygous for the variant and a pathogenic variant based on the ClinGen LSD VCEP's specifications (PM3) and the other is compound heterozygous for the variant and a pathogenic or likely pathogenic variant that has not been assessed according to the ClinGen LSD VCEP's specifications. The highest population minor allele frequency in gnomAD is 0.00004 (3/74944 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion. When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.7% GAA activity in cells and 0.1% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3. The computational predictor REVEL gives a score of 0.757 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.670C>T, p.Arg224Trp] [ClinVar Variation ID:186994] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 646875, 2-star review status) with 5 submitters classifying the variant as likely pathogenic (3) or pathogenic (2). 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 Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PS3_moderate, PP3, PM5 (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.757 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).
• PM5: Another missense variant [c.670C>T, p.Arg224Trp] [ClinVar Variation ID:186994] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5).
• PM3: This variant was found in compound heterozygosity (phase unknown) with a unique pathogenic variant in GAA in one patient with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications (PMID: 23000108). Additional cases have been reported (PMID: 22002441, 22644586) but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting.
• PP4_Moderate: One individual (PMID: 23000108, 23147228, 22002441) has been reported with this variant and GAA activity in the affected range in a clinically validated dried blood spot assay. This meets the criteria for PP4. It has also been reported in two individuals described as having late-onset Pompe disease after positive newborn screening in Taiwan. There is no additional information and neither patient is on ERT.
• PM2_Supporting: The highest population minor allele frequency in gnomAD is 0.00004 (3/74944 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
• PS3_Moderate: When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.7% GAA activity in cells and 0.1% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3.

Approved on: 2023-12-19

Published on: 2023-12-22