Variant: NM_000152.4(GAA):c.1942G>A (p.Gly648Ser)

CA274102

188902 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 2485e980-b2ce-432e-871f-861aec685091

Approved on: 2020-04-21

Published on: 2020-05-28

HGVS expressions

NM_000152.4:c.1942G>A
NM_000152.4(GAA):c.1942G>A (p.Gly648Ser)
NC_000017.11:g.80112929G>A
CM000679.2:g.80112929G>A
NC_000017.10:g.78086728G>A
CM000679.1:g.78086728G>A
NC_000017.9:g.75701323G>A
NG_009822.1:g.16374G>A
ENST00000570803.6:c.1942G>A
ENST00000572080.2:c.*80G>A
ENST00000577106.6:c.1942G>A
ENST00000302262.8:c.1942G>A
ENST00000302262.7:c.1942G>A
ENST00000390015.7:c.1942G>A
ENST00000570716.1:n.382G>A
ENST00000572080.1:c.361G>A
ENST00000572803.1:n.556G>A
NM_000152.3:c.1942G>A
NM_001079803.1:c.1942G>A
NM_001079804.1:c.1942G>A
NM_001079803.2:c.1942G>A
NM_001079804.2:c.1942G>A
NM_000152.5:c.1942G>A
NM_001079803.3:c.1942G>A
NM_001079804.3:c.1942G>A

Pathogenic

• Met criteria codes: PS3 PP3 PP4 PM2 PM3

• Not Met criteria codes: PM5

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.1942G>A (p.Gly648Ser), has been reported in at least six patients with Pompe disease with residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962). Of these patients, one is compound heterozygous for the variant and c.-32-13T>G (PMID 9535769), one is heterozygous for the variant and c.2646+2T>A (PMID 29422078), and two are homozygous for the variant (PMIDs 26497565, 30214072), meeting PM3. Another patient is compound heterozygous for the variant and c.1076-22T>G (PMID 17573812), however, this in trans data will be used in the assessment of c.1076-22T>G and will not be included here in order to avoid a circular argument. Of note, there is a high incidence of this variant in the Maroon population of French Guiana (PMID 29637184). Of 12 patients with “enzymatically confirmed” infantile-onset Pompe disease, 9 were compound heterozygous for p.Gly648Ser and p.Arg854Ter. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00034 in the South Asian population, meeting PM2. When this variant was expressed in SV40_immortalized GAA deficient fibroblasts, the GAA activity was "negligible" (PMID 9535769), meeting PS3. The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function, meeting PP3. Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID 188902, 2 star review status) with one submitter classifying the variant as pathogenic and another as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PP3, PP4.

Met criteria codes

• PS3: When expressed in SV40_immortalized GAA deficient fibroblasts, the enzyme activity was "negligible" (PMID 9535769), meeting PS3.
• PP3: REVEL (in silico meta predictor for missense changes) score = 0.98 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion.
• PP4: At least six individuals with activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated assay have been reported (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962), meeting the specifications for PP4.
• PM2: This variant has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00034 (S. Asian), meeting the ClinGen LSD VCEP's threshold for PM2 (<0.001).
• PM3: At least six individuals with this variant have been reported to have Pompe disease and residual GAA activity meeting the specifications for PP4. Of these patients, one is compound heterozygous for the variant and c.-32-13T>G (PMID 9535769)(0.5 points), one is heterozygous for the variant and c.2646+2T>A (PMID 29422078)(0.25 points), and two are homozygous for the variant (PMIDs 26497565, 30214072) (0.5 points each). Another is compound heterozygous for the variant and c.1076-22T>G (PMID 17573812); note that this in trans data will be used in the assessment of c.1076-22T>G and will not be included here in order to avoid a circular argument. A total of 1.75 points was given, meeting PM3.

Not Met criteria codes

• PM5: Another amino acid substitution at the same position has been reported, c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument).