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.854C>G (p.Pro285Arg)

CA358045

225114 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: fdbef722-4167-4550-b57b-0d4d751a35b3
Approved on: 2024-07-21
Published on: 2024-12-06

HGVS expressions

NM_000152.5:c.854C>G
NM_000152.5(GAA):c.854C>G (p.Pro285Arg)
NC_000017.11:g.80107718C>G
CM000679.2:g.80107718C>G
NC_000017.10:g.78081517C>G
CM000679.1:g.78081517C>G
NC_000017.9:g.75696112C>G
NG_009822.1:g.11163C>G
ENST00000570803.6:c.854C>G
ENST00000572080.2:c.854C>G
ENST00000577106.6:c.854C>G
ENST00000302262.8:c.854C>G
ENST00000302262.7:c.854C>G
ENST00000390015.7:c.854C>G
ENST00000570803.5:c.854C>G
NM_000152.3:c.854C>G
NM_001079803.1:c.854C>G
NM_001079804.1:c.854C>G
NM_000152.4:c.854C>G
NM_001079803.2:c.854C>G
NM_001079804.2:c.854C>G
NM_001079803.3:c.854C>G
NM_001079804.3:c.854C>G
More

Likely Pathogenic

Met criteria codes 6
PM3_Supporting PP3 PP4_Moderate PM5_Supporting PM2_Supporting PS3_Supporting
Not Met criteria codes 1
PS1

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.854C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 285 (p.Pro285Arg). The highest population minor allele frequency in gnomAD v4.0.1 is 0.000001784 (1/ 1120816 alleles) in the European non-finish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant has been detected in at least three individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and pathogenic or likely pathogenic variants (c.1655T>C/p.Leu552Pro and c.2303C>T/Pro768Leu, none of those were confirmed in trans). 0.75 points (PMID: 28196920, 19862843). (PM3_Supporting). At least two probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant, both with documented deficiency of GAA activity (PMID: 28196920, 19862843). One proband had juvenile-onset (after 1 year of age) (PMID: 14695532). (PP4_Moderate). Expression of the variant in COS cell type resulted in 2-10% (~ 5%) of wild-type GAA activity and evidence of abnormal GAA synthesis and processing (PMID: 19862843, 14695532, 19862843). The variant was described as Class C (“less severe”), indicating that this variant may impact protein function (PMID: 14695532) (PS3_Supporting). The computational predictor REVEL gives a score of 0.883, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.853C>T, p.Pro285Ser) (PMID: 18425781, 21484825, 21550241; ClinVar Variation ID 281052) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 526532; 2-star review status) with four submitters classifying the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Supporting, PS3_Supporting, PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting.
Met criteria codes
PM3_Supporting
This variant has been detected in at least three individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and pathogenic or likely pathogenic variants (c.1655T>C/p.Leu552Pro and c.2303C>T (Pro768Leu), none of those were confirmed in trans). 0.5 points were given total, to avoid counting the same patient in 14695532 and 12213618, and excluding NBS NGS paper (PMID: 28196920, 12213618, 14695532, 19862843). (PM3_Supporting).
PP3
The computational predictor REVEL gives a score of 0.883 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).
PP4_Moderate
At least two probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant, two with documented deficiency of GAA activity (PMID: 28196920, 19862843) (PP4_Moderate). One proband had juvenile-onset (after 1 year of age) (PMID: 14695532).
PM5_Supporting
Another missense variant (c.853C>T, p.Pro285Ser) (PMID: 18425781, 21484825, 21550241; ClinVar Variation ID 281052) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting).
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.0.1 is 0.000001784 (1/ 1120816 alleles) in the European non-finish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting criterion PM2_Supporting.
PS3_Supporting
Expression of the variant in COS cell type resulted in 2-10% (~ 5%) of wild-type GAA activity, and evidence of abnormal GAA synthesis and processing (PMID: 19862843, 14695532, 19862843). The variant was described as Class C (“less severe”), indicating that this variant may impact protein function (PMID: 14695532) (PS3_Supporting).
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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