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.1669A>T (p.Ile557Phe)

CA401368911

558634 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: ba123cf8-84ca-4dc2-a485-78f138703aa2
Approved on: 2022-03-01
Published on: 2022-07-11

HGVS expressions

NM_000152.5:c.1669A>T
NM_000152.5(GAA):c.1669A>T (p.Ile557Phe)
NC_000017.11:g.80112015A>T
CM000679.2:g.80112015A>T
NC_000017.10:g.78085814A>T
CM000679.1:g.78085814A>T
NC_000017.9:g.75700409A>T
NG_009822.1:g.15460A>T
ENST00000570803.6:c.1669A>T
ENST00000572080.2:c.1669A>T
ENST00000577106.6:c.1669A>T
ENST00000302262.8:c.1669A>T
ENST00000302262.7:c.1669A>T
ENST00000390015.7:c.1669A>T
ENST00000572080.1:c.57A>T
ENST00000572803.1:n.283A>T
NM_000152.3:c.1669A>T
NM_001079803.1:c.1669A>T
NM_001079804.1:c.1669A>T
NM_000152.4:c.1669A>T
NM_001079803.2:c.1669A>T
NM_001079804.2:c.1669A>T
NM_001079803.3:c.1669A>T
NM_001079804.3:c.1669A>T
More

Likely Pathogenic

Met criteria codes 4
PS3_Moderate PP4_Moderate PM3 PM2_Supporting
Not Met criteria codes 3
BP4 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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.1669A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 557 (p.Ile557Phe). Three probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMIDs 23884227, 25612604, clinical laboratory data), two with documented deficiency of GAA activity (PMIDs 23884227, 25612604) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.1978C>T (p.Arg660Cys) (clinical laboratory data); the variants are confirmed in trans by parental testing. The other two patients are compound heterozygous for the variant and a variant classified as uncertain significance by the ClinGen LSD VCEP, either c.2132C>G (p.Thr711Arg) or c.1385T>C (p.Leu462Pro). The allelic data for these latter two patients will be used in the assessment of p.Thr711Arg or p.Leu462Pro and is not included here to avoid circular logic (PM3). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants; one asymptomatic and compound heterozygous for the variant and p.Thr711Arg (PMID: 20080426), and the other heterozygous for the variant and presumably unaffected (PMID 31076647). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 2.7% GAA activity in cells and 0.3% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1669A>G (p.Ile557Val) (ClinVar Variation ID: 856959) and c.1670T>G (p.Ile557Ser) (PMID: 26474166), in the same codon have been reported in patients with Pompe disease. However, these variants have been classified as variants of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 558634; 1 star review status) with one submitter classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. 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 LSD VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting. (Approved by LSD VCEP on Feb 15, 2022).
Met criteria codes
PS3_Moderate
Expression of the variant in COS7 or HEK293 cells resulted in 2.7% GAA activity in cells and 0.3% in medium, and evidence of abnormal synthesis and processing on Western blot leading the variant to be described as Class B (“potentially less severe”), and indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate).
PP4_Moderate
Three probands with symptoms consistent with infantile-onset-Pompe disease have been reported (PMIDs 23884227, 25612604, clinical laboratory data), two with documented deficiency of GAA activity (PMIDs 23884227, 25612604) (PP4_Moderate). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants (PMID 20080426, 31076647).
PM3
Of three probands with infantile onset Pompe disease, one is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.1978C>T (p.Arg660Cys); the variants are confirmed in trans by parental testing (1 point). The other two patients are compound heterozygous for the variant and a variant classified as uncertain significance by the ClinGen LSD VCEP, either p.Thr711Arg or c.1385T>C (p.Leu462Pro). The allelic data for these latter two patients will be used in the assessment of p.Thr711Arg or p.Leu462Pro and is not included here to avoid circular logic. Total points: 1 point (PM3). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants; one asymptomatic and compound heterozygous for the variant and p.Thr711Arg (PMID: 20080426), and the other heterozygous for the variant and presumably unaffected (PMID 31076647).
PM2_Supporting
This variant is absent in gnomAD v2.1.1. (PM2_Supporting).
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.
PP3
The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.
PM5
Two other missense variants, c.1669A>G (p.Ile557Val) (ClinVar Variation ID: 856959) and c.1670T>G (p.Ile557Ser) (PMID: 26474166), in the same codon have been reported in patients with Pompe disease. However, these variants have been classified as variants of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength.
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.