Variant: NM_000152.5(GAA):c.1392G>C (p.Arg464Ser)

CA8815303

432217 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 5ff4c67a-40fc-4de5-ac2f-2d74e46aee54

Approved on: 2022-09-19

Published on: 2022-09-19

HGVS expressions

NM_000152.5:c.1392G>C
NM_000152.5(GAA):c.1392G>C (p.Arg464Ser)
NC_000017.11:g.80110010G>C
CM000679.2:g.80110010G>C
NC_000017.10:g.78083809G>C
CM000679.1:g.78083809G>C
NC_000017.9:g.75698404G>C
NG_009822.1:g.13455G>C
ENST00000302262.8:c.1392G>C
ENST00000302262.7:c.1392G>C
ENST00000390015.7:c.1392G>C
NM_000152.3:c.1392G>C
NM_001079803.1:c.1392G>C
NM_001079804.1:c.1392G>C
NM_000152.4:c.1392G>C
NM_001079803.2:c.1392G>C
NM_001079804.2:c.1392G>C
NM_001079803.3:c.1392G>C
NM_001079804.3:c.1392G>C

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: PP3 PM5 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_000152.5c.1392G>C variant in GAA is a missense variant predicted to cause substitution of Arginine by Serine at amino acid 464 (p.Arg464Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (13/128364 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. The computational predictor REVEL gives a score of 0.634 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Another missense variant c.1390A>T, p.Arg464Trp in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 843677). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP. There is a ClinVar entry for this variant (Variation ID: 432217, 1 star review status) with 4 submitters classifying the variant as Uncertain Significance and 1 submitter classifying the variant as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain Significance 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): PM2_Supporting.

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (13/128364 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

• PP3: The computational predictor REVEL gives a score of 0.634 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.
• PM5: Another missense variant c.1390A>T, p.Arg464Trp in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 843677). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met).
• PM3: A patient with suspected LOPD based on newborn screening was heterozygous for this variant and an additional variant c.784G>A. However, confirmatory GAA activity testing result of 4.00 (N>3.88) suggested that GAA activitiy is not deficient (PMID: 33202836).