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The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000152.5(GAA):c.1124G>T (p.Arg375Leu)

CA8815178

283230 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: ea5eeffe-15f9-49be-9b02-6863bf2ea91b
Approved on: 2022-09-20
Published on: 2022-12-20

HGVS expressions

NM_000152.5(GAA):c.1124G>T
NM_000152.5:c.1124G>T
NM_000152.5(GAA):c.1124G>T (p.Arg375Leu)
NC_000017.11:g.80108537G>T
CM000679.2:g.80108537G>T
NC_000017.10:g.78082336G>T
CM000679.1:g.78082336G>T
NC_000017.9:g.75696931G>T
NG_009822.1:g.11982G>T
ENST00000302262.8:c.1124G>T
ENST00000302262.7:c.1124G>T
ENST00000390015.7:c.1124G>T
NM_000152.3:c.1124G>T
NM_001079803.1:c.1124G>T
NM_001079804.1:c.1124G>T
NM_000152.4:c.1124G>T
NM_001079803.2:c.1124G>T
NM_001079804.2:c.1124G>T
NM_001079803.3:c.1124G>T
NM_001079804.3:c.1124G>T
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Likely Pathogenic

Met criteria codes 5
PS3_Supporting PP4_Moderate PM2_Supporting PP3 PM3_Strong
Not Met criteria codes 1
PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID: 18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID: 21757382, 21484825) . 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). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) 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 Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022)
Met criteria codes
PS3_Supporting
Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity. There was hardly any GAA protein detectable on western blot of this mutant construct (PMID: 18429042) (PS3_supporting).
PP4_Moderate
One late-onset Pompe patient from Italy with GAA genotype [c.-32-13T>G/c.1124G>T (p.Arg375Leu)] documented leukocyte GAA residual activity as 21.98% and muscle GAA activity to be 5.95% (PMID: 24158270). Two late onset Pompe patients from Italy on ERT, confirmed diagnosis with reduced GAA activity below 35% of controls in skeletal muscle, leukocytes or fibroblasts (PMID: 22081099). Two severe infantile Pompe cases, diagnosed based on clinical data including mycardiopathy and severe hypotonia and confirmed by reduced GAA activity in different tissues of fibroblasts and/ or blood samples (PMID: 18429042).
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 (Exomes) is 0.00001787 (2/111942 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).
PP3
The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3)
PM3_Strong
This variant has been detected in at least 4 individuals with Pompe disease. Of those, three late onset Pompe patient are documented to be compound heterozygous for the variant c.1124G>T (p.Arg375Leu) and the pathogenic varint c.-32-13T>G in GAA. Phase unknown (max 2 x 0.5) (PMID: 24158270; PMID: 22081099) (total 1 point; one patient possibly common in both publications from Italy). Two probands with severe infantile Pompe disease harbor the variant; one proband is compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed to be present on alternate alleles by DNA analysis of parents/relatives (1 point), one infant is homozygous for c.1124G>T(p.Arg375Leu). 0.5 point. Total points: 2.5 (PM3_strong).
Not Met criteria codes
PM5
Another missense variant [c.1124G>A(p. Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID: 21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP.
Curation History
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