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


Variant: NM_000152.5(GAA):c.1437+1G>A

CA401366675

555864 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: 9a6345f6-7429-478a-b1cd-425d37ecbfde
Approved on: 2023-05-16
Published on: 2023-11-03

HGVS expressions

NM_000152.5(GAA):c.1437+1G>A
NM_000152.5:c.1437+1G>A
NC_000017.11:g.80110056G>A
CM000679.2:g.80110056G>A
NC_000017.10:g.78083855G>A
CM000679.1:g.78083855G>A
NC_000017.9:g.75698450G>A
NG_009822.1:g.13501G>A
ENST00000302262.8:c.1437+1G>A
ENST00000302262.7:c.1437+1G>A
ENST00000390015.7:c.1437+1G>A
NM_000152.3:c.1437+1G>A
NM_001079803.1:c.1437+1G>A
NM_001079804.1:c.1437+1G>A
NM_000152.4:c.1437+1G>A
NM_001079803.2:c.1437+1G>A
NM_001079804.2:c.1437+1G>A
NM_001079803.3:c.1437+1G>A
NM_001079804.3:c.1437+1G>A
More

Likely Pathogenic

Met criteria codes 4
PP4_Moderate PVS1_Strong PM2_Supporting 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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.1437+1G>A, alters the donor splice site of intron 9. Based on RT-PCR results from a patient who is compound heterozygous for the variant, this results in skipping of exon 9, which leads to an in frame deletion of p.Asp443_Lys479del (PMID 22676651), including part of the GAA catalytic barrel (PMID 22253258). Western blot analysis of protein extracted from cultured skin fibroblasts from a patient who is homozygous for the variant revealed that the patient was positive from cross-reactive immunological material, supporting that the variant results in an in-frame consequence (PMID 22252923). Based on these results, PVS1_Strong was applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, meeting PM2_Supporting. Two patients with Pompe disease have been reported who are homozygous for the variant and meet the ClinGen LSD VCEP's PP4 specifications (PMID 22555271, 22252923; personal communication), meeting PM3 and PP4_Moderate. Another patient has been reported with the variant in trans with c.1076-22G>A (PMID 22676651). In trans data from this patient will be used in the assessment of c.1076-22G>A and is not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 555864; two star review status) with five submitters classifying the variant as pathogenic and one submitter classifying as likely pathogenic. In summary, 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 LSD VCEP (Specifications Version 2.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Moderate.
Met criteria codes
PP4_Moderate
At least 3 patient(s) with this variant were noted to have deficient GAA activity but results were not provided or were diagnosed with infantile Pompe disease (PMIDs 22252923, 22676651, 22555271) (PP4_Moderate).
PVS1_Strong
This variant alters the donor splice site of intron 9. This has been shown to result in skipping of exon 9, which leads to an in frame deletion, p.Asp443_Lys479del (PMID 22676651). Exon 9 forms part of the GAA catalytic barrel (PMID 22253258). Western blot analysis of protein extracted from cultured skin fibroblasts from a patient who is homozygous for the variant revealed that protein is made (i.e. the patient was CRIM-positive), suggesting that this variant results in an inframe consequence (PMID 22252923). PVS1_Strong will be applied based on the specifications of the ClinGen LSD VCEP.
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002895 (1/34538 alleles) in the Latino population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
PM3
A patient with Pompe disease was reported who is homozygous for the variant and meets the ClinGen LSD VCEP's PP4 specifications (PMID 22252923; personal communication). This data was awarded 0.5 points based on the specifications of the ClinGen LSD VCEP, meeting PM3_Supporting. Another patient has been reported with the variant in trans with c.1076-22G>A (PMID 22676651). In trans data from this patient will be used in the assessment of c.1076-22G>A and is not included here in order to avoid a circular argument.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.