Variant: NM_000152.5(GAA):c.1048G>A (p.Val350Met)

CA8815133

555998 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 9dbf33c0-fff9-4a3f-a78e-ff4de92b7499

Approved on: 2024-03-19

Published on: 2024-03-27

HGVS expressions

NM_000152.5:c.1048G>A
NM_000152.5(GAA):c.1048G>A (p.Val350Met)
NC_000017.11:g.80108382G>A
CM000679.2:g.80108382G>A
NC_000017.10:g.78082181G>A
CM000679.1:g.78082181G>A
NC_000017.9:g.75696776G>A
NG_009822.1:g.11827G>A
ENST00000570803.6:c.1048G>A
ENST00000572080.2:c.1048G>A
ENST00000577106.6:c.1048G>A
ENST00000302262.8:c.1048G>A
ENST00000302262.7:c.1048G>A
ENST00000390015.7:c.1048G>A
NM_000152.3:c.1048G>A
NM_001079803.1:c.1048G>A
NM_001079804.1:c.1048G>A
NM_000152.4:c.1048G>A
NM_001079803.2:c.1048G>A
NM_001079804.2:c.1048G>A
NM_001079803.3:c.1048G>A
NM_001079804.3:c.1048G>A

Uncertain Significance

• Met criteria codes: PS3_Supporting PP3 PM2_Supporting

• Not Met criteria codes: PP4 PM3

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(GAA):c.1048G>A variant in GAA is a missense variant predicted to cause substitution of valine by methionine at amino acid 350 (p.Val350Met). This variant has been detected in at least 12 individuals, and at least 11 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (Clinical Laboratory data, PMIDs: 25451853, 36310651, 36246652). However, in the absence of clinical symptoms to support that the variant causes Pompe disease, PP4 was not applied. Of those individuals, 1 was homozygous for the variant, and 11 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant in GAA; 2 of those were confirmed in trans by parental testing, including c.-32-13T>G (9 patients, Clinical laboratory data, PMID:25451853, 1 patient confirmed in trans), c.2051C>T (p.Pro684Leu) (1 patient, PMID:36310651, phase unknown), c.1589del (p.Glu530GlyfsTer48) (1 patient, PMID: 36246652, phase unknown), and c.2238G>C (p.Trp746Cys) (2 patients, one confirmed in trans and one with a pseudodeficiency allele, Clinical Laboratory data). Due to lack of clinical symptoms in these patients, PM3 is not met at the current time. When expressed in HEK293 cells, GAA enzyme activity was 1.5% of the positive control (Table 3). Western blot revealed faint precursor (110 k Da) and mature (76 kDa) protein bands with lower intensity compared to the positive control, indicating this variant may be impacting GAA protein stability and processing (PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00013 (17/1128822 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). 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: 555998). In summary, while patients with this variant have been reported with deficiency GAA activity, and the variant has been found in compound heterozygosity with pathogenic and likely pathogenic variants in GAA, the Lysosomal Diseases VCEP concluded that there is insufficient phenotypic evidence to indicate that this variant cuases Pompe disease at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PS3_Supporting, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).

Met criteria codes

• PS3_Supporting: When expressed in HEK293 cells GAA enzyme activity was 1.5% of the positive control (Table 3). Western blot revealed faint precursor (110 k Da) and mature (76 kDa) protein bands with lower intensity compared to the positive control, indicating this variant may be impacting GAA protein stability and processing (PS3_Supporting).
• 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).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00013 (17/1128822 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PP4: At least 11 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (Clinical laboratory data, PMIDs: 25451853, 36310651, 36246652). However, in the absence of clinical symptoms to support that the variant causes Pompe disease, PP4 was not applied.
• PM3: This variant has been detected in at least 12 individuals. Of those individuals, 1 was homozygous for the variant, and 11 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant in GAA; 2 of those were confirmed in trans by parental testing, including c.-32-13T>G (9 patients, Clinical laboratory data, PMID:25451853, 1 patient confirmed in trans), c.2051C>T (p.Pro684Leu) (1 patient, PMID:36310651, phase unknown), c.1589del (p.Glu530GlyfsTer48) (1 patient, PMID: 36246652, phase unknown), and c.2238G>C (p.Trp746Cys) (2 patients, one confirmed in trans and one with a pseudodeficiency allele, Clinical Laboratory data). Due to lack of clinical symptoms in these patients, no points were given for PM3; PM3 is not met at the current time.