Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000152.5(GAA):c.841C>T (p.Arg281Trp)

CA8815025

283894 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 6a43fe2d-1dea-4a99-bb53-737388ab566c
Approved on: 2024-04-08
Published on: 2024-04-08

HGVS expressions

NM_000152.5:c.841C>T
NM_000152.5(GAA):c.841C>T (p.Arg281Trp)
NC_000017.11:g.80107705C>T
CM000679.2:g.80107705C>T
NC_000017.10:g.78081504C>T
CM000679.1:g.78081504C>T
NC_000017.9:g.75696099C>T
NG_009822.1:g.11150C>T
ENST00000570803.6:c.841C>T
ENST00000572080.2:c.841C>T
ENST00000577106.6:c.841C>T
ENST00000302262.8:c.841C>T
ENST00000302262.7:c.841C>T
ENST00000390015.7:c.841C>T
ENST00000570803.5:c.841C>T
NM_000152.3:c.841C>T
NM_001079803.1:c.841C>T
NM_001079804.1:c.841C>T
NM_000152.4:c.841C>T
NM_001079803.2:c.841C>T
NM_001079804.2:c.841C>T
NM_001079803.3:c.841C>T
NM_001079804.3:c.841C>T

Likely Pathogenic

Met criteria codes 4
PP3 PP4_Moderate PM3_Strong PM2_Supporting
Not Met criteria codes 2
PS3 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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.841C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 281 (p.Arg281Trp). This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID: 36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID: 31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID: 33202836), as well as in five individuals reported to have later-onset disease (PMID: 22081099, 33073009) (PP4_Moderate). Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID: 36299500, phase unknown) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID: 33202836; phase unknown) (ClinVar Variation ID: 4027) (PM3_Strong). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2_Supporting. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894). This variant meets the criteria to the classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2019. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 8, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.786 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). SpliceAI predicts that the variant has no impact on splicing.
PP4_Moderate
This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID: 36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID: 31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID: 33202836), as well as in five individuals reported to have later-onset disease (PMID: 22081099, 33073009) (PP4_Moderate).
PM3_Strong
Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID: 36299500, phase unknown, 0.5 points) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown, 0.5 points) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans; 1 point) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID: 33202836; phase unknown, 0.5 points) (ClinVar Variation ID: 4027). The variant has been reported in additional individuals where PM3 does not apply (PMID 2208109, 23430949, 31086307). 2.5 points were given, meeting PM3_Strong.
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (51/125884 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).
Not Met criteria codes
PS3
No published functional studies, in which the variant was expressed in a heterologous cell type, were identified.
PM5
Another variant at the same amino acid position has been reported in a patient with Pompe disease, c.842G>C p.(Arg281Pro) (PMID: 36245745). This data will be used in the classification of c.842G>C p.(Arg281Pro) and is not included here to avoid circular logic.
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