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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000152.5(GAA):c.796C>T (p.Pro266Ser)

CA401363495

556117 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 2b5077ea-d72a-4564-a83c-2aea98c3b4a8
Approved on: 2025-06-03
Published on: 2025-07-30

HGVS expressions

NM_000152.5:c.796C>T
NM_000152.5(GAA):c.796C>T (p.Pro266Ser)
NC_000017.11:g.80107660C>T
CM000679.2:g.80107660C>T
NC_000017.10:g.78081459C>T
CM000679.1:g.78081459C>T
NC_000017.9:g.75696054C>T
NG_009822.1:g.11105C>T
ENST00000570803.6:c.796C>T
ENST00000572080.2:c.796C>T
ENST00000577106.6:c.796C>T
ENST00000302262.8:c.796C>T
ENST00000302262.7:c.796C>T
ENST00000390015.7:c.796C>T
ENST00000570803.5:c.796C>T
NM_000152.3:c.796C>T
NM_001079803.1:c.796C>T
NM_001079804.1:c.796C>T
NM_000152.4:c.796C>T
NM_001079803.2:c.796C>T
NM_001079804.2:c.796C>T
NM_001079803.3:c.796C>T
NM_001079804.3:c.796C>T
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Likely Pathogenic

Met criteria codes 5
BP4 PS3_Supporting PP4_Moderate PM2_Supporting PM3_Strong
Not Met criteria codes 3
PS1 PP3 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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.796C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 266 (p.Pro266Ser). At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented laboratory values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014) (PP4_Moderate). These patients are all compound heterozygous for the variant and another variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175,), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001333 (1/70356 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843). Additional variants at this amino acid positions have been reported (c.797C>T (p.Pro266Leu); c.796C>A (p.Pro266Thr) (PMID: 29451150); these variants have not been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. The score from the in silico metapredictor REVEL is 0.476 (BP4), which is a single piece of conflicting evidence in comparison with the evidence for pathogenicity. There is a ClinVar entry for this variant (Variation ID:556117, 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, based on the overall evidence, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 3, 2025)
Met criteria codes
BP4
REVEL score = 0.476 which is lower than the LD VCEP threshold for BP4 (<0.5), and therefore meets this criterion.
PS3_Supporting
This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843).
PP4_Moderate
At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014) (PP4_Moderate).
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001333 (1/70356 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
PM3_Strong
Seven patients with features consistent with Pompe disease are compound heterozygous for the variant and a variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786; 0.5 points), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175, 2 x 0.5 points), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1) (0.5 points), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1) (2 x 0.5 points), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (0.25 points). Total 3.25 points (PM3_Strong).
Not Met criteria codes
PS1
The p.Pro266Ser amino acid change has not been reported with another nucleotide change in ClinVar, HGMD Pro, LOVD or pompevariantdatabase.nl.
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
A missense change (p.Pro266Leu, c.797C>T) at the same amino acid residue has been reported by ClinVar. Another missense change (p.Pro266Thr, c.796C>A) at the same amino acid residue is reported in literature. These variants have not been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. Therefore, PM5 is not met.
Curation History
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