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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000152.5(GAA):c.655G>A (p.Gly219Arg)

CA274334

189065 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 0ef0c8e1-2dac-4aa5-b960-5bedcbc50b26
Approved on: 2020-04-19
Published on: 2020-05-26

HGVS expressions

NM_000152.5:c.655G>A
NM_000152.5(GAA):c.655G>A (p.Gly219Arg)
NC_000017.11:g.80105857G>A
CM000679.2:g.80105857G>A
NC_000017.10:g.78079656G>A
CM000679.1:g.78079656G>A
NC_000017.9:g.75694251G>A
NG_009822.1:g.9302G>A
NM_000152.3:c.655G>A
NM_001079803.1:c.655G>A
NM_001079804.1:c.655G>A
NM_000152.4:c.655G>A
NM_001079803.2:c.655G>A
NM_001079804.2:c.655G>A
NM_001079803.3:c.655G>A
NM_001079804.3:c.655G>A
ENST00000302262.7:c.655G>A
ENST00000390015.7:c.655G>A
ENST00000570803.5:c.655G>A
More

Pathogenic

Met criteria codes 5
PM2 PM3_Strong PS3 PP4 PP3

Evidence Links 18

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.655G>A (p.Gly219Arg), has been reported in at least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, including c.-32-13T>G (PMID 21550241, 24844452), c.169C>T (p.Gln57Ter) (PMID 29124014), or c.2560C>T (p.Arg854Ter)(PMID 23266370), and one is homozygous for the variant (PMID 25139343). This in trans data meets PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004024 in the African population, meeting PM2. When it was expressed in COS cells, this variant results in <2% wild type GAA activity and it is abnormally processed (PMIDs 14695532; 19862843), meeting PS3. The score for the REVEL in silico meta-predictor, 0.872, also supports that the variant has a deleterious impact on GAA function, meeting PP3. There is a ClinVar entry for this variant (Variation ID 189065; 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 pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4.
Met criteria codes
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004024 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
PM3_Strong
At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607).
PubMed:23787031
PubMed:31193175
PubMed:25139343
PubMed:11738358
PubMed:23266370
PubMed:21550241
PubMed:30155607
PubMed:18429042
PubMed:14695532
PubMed:29289479
PubMed:20033296
PubMed:24844452
PubMed:27711114
PubMed:30023291
PubMed:25037089
PubMed:29124014
PubMed:23601496
PS3
This variant results in <2% GAA activity and is abnormally processed when expressed in COS cells (PMIDs 14695532; 19862843) meeting the ClinGen LSD VCEP specifications for PS3.
The variant was introduced into GAA cDNA by site directed mutagenesis and transfected into COS cells which were harvested 72 hours later. GAA activity in cells using 4-MU as a substrate was 0.5%, and in medium 0% of normal. GAA activity in cells using glycogen as a substrate was 0.5% of normal (Table 2). On Western blot, an abnormal processing pattern was noted, with production of the 110 kDa precursor protein, but only a very faint 95 kDa intermediate band, and no detectable 76 kDa (active) band. Controls used were normal GAA cDNA and mock transfection. No information was provided regarding the number of repetitions of the experiment or whether the inserts were sequenced. PubMed:14695532
The variant was introduced into GAA cDNA by site directed mutagenesis and subcloned into a plasmid vector (note that only the amino acid change is provided in the paper; the cDNA change is not provided). The integrity of the insert was verified by sequencing. COS cells transfected with the variant had GAA activity of <2% of normal. The data was compiled from two or more independent transfections. Controls used included mock transfected cells (negative control) and wild type cDNA (positive control). PubMed:19862843
PP4
Eight individuals have been reported with this variant and GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay (PMIDs 11738358, 20033296, 23266370, 23601496, 24844452, 25037089, 25139343, 29124014). This meets the specifications for PP4.
PP3
REVEL score = 0.872 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion.
Curation History
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