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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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_000152.5(GAA):c.971C>T (p.Pro324Leu)

CA8815119

431990 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 29286c8a-05c7-42ee-a1cb-26203f99d1c4

HGVS expressions

NM_000152.5:c.971C>T
NM_000152.5(GAA):c.971C>T (p.Pro324Leu)
NC_000017.11:g.80108305C>T
CM000679.2:g.80108305C>T
NC_000017.10:g.78082104C>T
CM000679.1:g.78082104C>T
NC_000017.9:g.75696699C>T
NG_009822.1:g.11750C>T
ENST00000570803.6:c.971C>T
ENST00000572080.2:c.971C>T
ENST00000577106.6:c.971C>T
ENST00000302262.8:c.971C>T
ENST00000302262.7:c.971C>T
ENST00000390015.7:c.971C>T
NM_000152.3:c.971C>T
NM_001079803.1:c.971C>T
NM_001079804.1:c.971C>T
NM_000152.4:c.971C>T
NM_001079803.2:c.971C>T
NM_001079804.2:c.971C>T
NM_001079803.3:c.971C>T
NM_001079804.3:c.971C>T

Uncertain Significance

Met criteria codes 2
PP3 PM2_Supporting
Not Met criteria codes 3
PS3 PP4 PM3

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.971C>T variant in GAA is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 324 (p.Pro324Leu). One patient is reported to be compound heterozygous for the variant and c.794G>A (p.Ser265Asn). However the clinical symptoms were not consistent with Pompe disease. Another patient, with history of muscle weakness, had documented GAA deficiency in leukocytes after immunoprecipitation, 15% of normal mean control level, which does not meet the LD VCEP's threshold for PP4. IN addition, the cDNA changes for the variants in this patient was not provided, and therefore this data was not included (PMID:11071489) (PP4 not met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004014 (1/24914 alleles) in the African /African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.788 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3). When expressed in CHO cells, the variant has activity >2% normal but, because further details are not available regarding the activity of the variant, PS3 was not applied. There is a ClinVar entry for this variant (Variant ID: 431990). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease, based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications version 2.0): PM2_Supporting, PP3. (The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Oct. 4th, 2022. The classification was re-evaluated and re-approved on April 2, 2024).
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.788 which is above the threshold predicting a damaging (>0.7) impact on GAA function.
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004014 (1/24914 alleles) in the African /Afrincan American population, which is lower than the ClinGen LSD VCEP’s threshold for <0.001, meeting this criterion PM2_Supporting.
Not Met criteria codes
PS3
When expressed in CHO cells, the variant has activity >2% normal and was expressed as both precursor 110kDa and mature 76kDa form of GAA of reduced amount (PMIDs 19862843). However, because further details are not available regarding the activity of the variant, PS3 was not applied.
PP4
Two patients with this variant and a diagnosis of late onset Pompe disease have been reported (PMID: 11071489). One patient, from India, has documented deficiency of GAA activity in dried blood spot. However, his phenotype is not consistent with the diagnosis of Pompe disease (PMID: 34864681). The second patient, from France, has 15% GAA activity in leukocytes which is reduced but does not meet the LD VCEP's threshold for PP4. Furthermore, the cDNA changes for the variants were not provided for this patient (PMID: 11071489) (PP4 not met).
PM3
One patient is reported to be compound heterozygous for the variant and c.794G>A(p.Ser265Asn). However, the clinical phenotype for this patient is not consistent with Pompe disease ( PMID: 34864681). Another patient has been reported to be compound heterozygous the variant and p.Trp490Ter, phase unknown. The cDNA changes for these variants were not provided, and therefore this data is not included (PMID: 11071489).
Approved on: 2024-04-02
Published on: 2024-04-05
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