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_000152.4(GAA):c.925G>A (p.Gly309Arg)

CA273972

188797 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: de8ae80b-693a-4177-8218-1d731456b97c
Approved on: 2020-04-20
Published on: 2020-05-28

HGVS expressions

NM_000152.4:c.925G>A
NM_000152.4(GAA):c.925G>A (p.Gly309Arg)
NC_000017.11:g.80107866G>A
CM000679.2:g.80107866G>A
NC_000017.10:g.78081665G>A
CM000679.1:g.78081665G>A
NC_000017.9:g.75696260G>A
NG_009822.1:g.11311G>A
ENST00000570803.6:c.925G>A
ENST00000572080.2:c.925G>A
ENST00000577106.6:c.925G>A
ENST00000302262.8:c.925G>A
ENST00000302262.7:c.925G>A
ENST00000390015.7:c.925G>A
NM_000152.3:c.925G>A
NM_001079803.1:c.925G>A
NM_001079804.1:c.925G>A
NM_001079803.2:c.925G>A
NM_001079804.2:c.925G>A
NM_000152.5:c.925G>A
NM_001079803.3:c.925G>A
NM_001079804.3:c.925G>A
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Pathogenic

Met criteria codes 5
PS3 PP3 PP4 PM3_Strong PM2

Evidence Links 9

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.925G>A (p.Gly309Arg), has been reported in at least 5 patients with Pompe disease who meet the specifications for PP4 (PMIDs 16838077, 23430847, 23601496, 27189384, doi:10.21767/2380-7245.100010). One of these individuals is homozygous for the variant (PMID 23601496), and three individuals are compound heterozygous for the variant and a pathogenic variant in GAA; either c.-32-13T>G (PMID 16838077), c.2269C>T (p.Gln757Ter) (PMID 23430847), or c.2608C>T (p.Arg870Ter) (doi:10.21767/2380-7245.100010), meeting PM3_Strong. Additional patients have been reported but were not included because the residual GAA enzyme activity was not reported and therefore PP4 cannot be assessed (PMIDs 9660056, 16917947, 23402890, 24245577), a patient with the same genotype has already been included (PMID 24495340), or the cDNA sequence for the variant was not provided (PMID 17616415). When expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843), meeting PS3. The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00004544 in the European non-Finnish population, meeting PM2. The deleterious impact of this variant is also supported by the in silico meta-predictor, REVEL (score 0.963), meeting PP3. There is a ClinVar entry for this variant (Variation ID: 188797; 2 star review status) with 4 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4.
Met criteria codes
PS3
In two studies, when expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843), meeting PS3.
The variant was introduced into GAA cDNA by site directed mutagenesis and subcloned into a plasmid vector. The integrity of the insert was verified by sequencing. COS cells transfected with the variant had GAA activity of <2%. Controls used included mock transfected cells (negative control) and wild type cDNA (positive control). Data was compiled from two or more independent transfections of the variant. PubMed:19862843
When the variant was expressed in COS cells, there was no increase in GAA enzyme activity, whereas wild type GAA resulted in 10x enzyme activity. Pulse chase analysis showed that the 110kDa prescursor is not processed to the 95kDa intermediate ot 76kDa active forms. This is consistent with the processing defect noted on Western blot analysis of cultured fibroblasts from the patient. PubMed:9660056
PP3
REVEL (in silico meta predictor for missense changes) score = 0.963 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion.
PP4
At least three individuals have been reported with this variant and <10% normal GAA activity in lymphocytes or leukocytes, or <30% normal in cultured fibroblasts (PMIDs 16838077, 23430847, 23601496). This meets the specifications for PP4.
PubMed:24495340
PM3_Strong
This variant was found in at least 5 patients with Pompe disease who meet the specifications for PP4 (PMIDs 16838077, 23430847, 23601496, 27189384, doi:10.21767/2380-7245.100010). One of these individuals is homozygous for the variant (PMID 23601496), and three individuals are compound heterozygous for the variant and a pathogenic variant in GAA; either c.-32-13T>G (PMID 16838077), c.2269C>T (p.Gln757Ter) (PMID 23430847), or c.2608C>T (p.Arg870Ter) (doi:10.21767/2380-7245.100010), meeting PM3_Strong. Additional patients have been reported but were not included because the residual GAA enzyme activity was not reported and therefore PP4 cannot be assessed (PMIDs 9660056, 16917947, 23402890, 24245577), a patient with the same genotype has already been included (PMID 24495340), or the cDNA sequence for the variant was not provided (PMID 17616415).
PubMed:27189384
PubMed:16917947
PubMed:23601496
Five out of nine Dutch patients with infantile onset Pompe disease were heterozygous for c.925G>A (p.Gly309Arg); two of these patients were heterozygous for the known pathogenic variant c.525delT, and the other three were heterozygous for p.Gly828_Asn882del. An adult patient with late onset Pompe disease was compound heterozygous for c.925G>A (p.Gly309Arg) and the known pathogenic variant c.-32-13T>G. The phase of the variants is unknown. The GAA activity was not provided for these patients and therefore this data will not be included. PubMed:9660056
PubMed:23430847
PubMed:16838077
Case report of a patient presenting at 6 months of age with weakness, hypotonia, hepatomegaly and hypertrophic cardiomyopathy. DNA analysis revealed c.925G>A (p.Gly309Arg) in trans with a large deletion/insertion encompassing the entire GAA gene and a large fragment of CCDC40. GAA activity in dry blood spot was suggestive of Pompe disease but the specific value was not provided, and therefore this data will not be used. PubMed:23402890
PM2
The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00004544 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
Curation History
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