Variant: NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)

CA16041901

370223 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: ed960e3f-0822-43b8-8558-3a361d2331d7

HGVS expressions

NM_000152.5:c.2214G>A
NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)
NC_000017.11:g.80116992G>A
CM000679.2:g.80116992G>A
NC_000017.10:g.78090791G>A
CM000679.1:g.78090791G>A
NC_000017.9:g.75705386G>A
NG_009822.1:g.20437G>A
NM_000152.3:c.2214G>A
NM_001079803.1:c.2214G>A
NM_001079804.1:c.2214G>A
NM_000152.4:c.2214G>A
NM_001079803.2:c.2214G>A
NM_001079804.2:c.2214G>A
NM_001079803.3:c.2214G>A
NM_001079804.3:c.2214G>A
ENST00000302262.7:c.2214G>A
ENST00000390015.7:c.2214G>A
ENST00000572080.1:n.633G>A
ENST00000573556.1:n.167G>A

Pathogenic

• Met criteria codes: PM3_Supporting PP4 PM2 PVS1

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.2214G>A (p.Trp738Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, meeting PM2. An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). This data meets PM3_Supporting. In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). There is a ClinVar entry for this variant (Variation ID: 370223; 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

Met criteria codes

• PM3_Supporting: An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). This data meets PM3_Supporting.
• PP4: Twins have been reported with this variant and GAA activity in dried blood spots in the affected range in a clinically validated assay (PMID 26575883) and another patient has GAA activity in the affected range in lymphocytes (PMID 22676651). This meets the specifications for PP4.
• PM2: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
• PVS1: This is a nonsense variant which is predicted to cause nonsense mediated decay resulting in lack of gene product. Therefore, PVS1 can be applied.

Approved on: 2020-10-05

Published on: 2020-11-12