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

  • See Evidence submitted by expert panel for details.

Variant: NM_000152.5(GAA):c.525_526del (p.Asn177fs)

CA274328

189057 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: abc2a8a5-c942-42ac-9a92-4a7b9cede5c9

HGVS expressions

NM_000152.5:c.525_526del
NM_000152.5(GAA):c.525_526del (p.Asn177fs)
NM_000152.3:c.525_526del
NM_001079803.1:c.525_526del
NM_001079804.1:c.525_526del
NM_000152.4:c.525_526del
NM_001079803.2:c.525_526del
NM_001079804.2:c.525_526del
NM_001079803.3:c.525_526del
NM_001079804.3:c.525_526del
ENST00000302262.7:c.525_526del
ENST00000390015.7:c.525_526del
ENST00000570803.5:c.525_526del
ENST00000577106.5:c.525_526del
NC_000017.11:g.80105111_80105112del
CM000679.2:g.80105111_80105112del
NC_000017.10:g.78078910_78078911del
CM000679.1:g.78078910_78078911del
NC_000017.9:g.75693505_75693506del
NG_009822.1:g.8556_8557del

Pathogenic

Met criteria codes 4
PP4 PM2 PVS1 PM3_Supporting

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.525_526del (p.Asn177ProfsTer11), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of this variant in an individual with no GAA cross-reactive immunological material in cultured skin fibroblasts (PMID 22252923, 23825616, 31342611). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003288 in the South Asian population, meeting PM2. One individual with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied. There is a ClinVar entry for this variant (Variation ID: 189057, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Met criteria codes
PP4
One patient with Pompe disease meeting the ClinGen LSD VCEP's specifications for PP4 has been reported (PMID 23825616; personal communication).
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003288 in the South Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
PVS1
This is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This is supported by the finding of this variant in an individual with no GAA cross-reactive immunological material in cultured skin fibroblasts (PMID 22252923, 23825616, 31342611).
PM3_Supporting
One individual with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied.

Approved on: 2020-11-02
Published on: 2020-11-11
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