NM_000152.5(GAA):c.569G>A (p.Arg190His) AND Glycogen storage disease, type II

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Feb 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169143.14

Allele description

NM_000152.5(GAA):c.569G>A (p.Arg190His)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.569G>A (p.Arg190His)

HGVS:

NC_000017.11:g.80105771G>A
NG_009822.1:g.9216G>A
NM_000152.5:c.569G>AMANE SELECT
NM_001079803.3:c.569G>A
NM_001079804.3:c.569G>A
NP_000143.2:p.Arg190His
NP_001073271.1:p.Arg190His
NP_001073272.1:p.Arg190His
LRG_673t1:c.569G>A
LRG_673:g.9216G>A
NC_000017.10:g.78079570G>A
NM_000152.3:c.569G>A
NM_000152.4(GAA):c.569G>A
P10253:p.Arg190His

Protein change:

R190H

Links:

UniProtKB: P10253#VAR_068570; dbSNP: rs528367092

NCBI 1000 Genomes Browser:

rs528367092

Molecular consequence:

NM_000152.5:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glycogen storage disease, type II (GSD2)
Synonyms:: ACID ALPHA-GLUCOSIDASE DEFICIENCY; GLYCOGENOSIS, GENERALIZED, CARDIAC FORM; GSD II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009290; MedGen: C0017921; Orphanet: 365; OMIM: 232300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220363	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 31, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 24444888, 23000108, 22644586, 18425781 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000919379	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 2, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18425781, 23000108, 29124014, 21484825 Citation Link,
SCV001226092	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21484825, 23000108, 24444888, 29149851, 31076647, 29046207, 28492532
SCV001422620	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 22644586, 23000108, 24444888, 25741868 Citation Link,
SCV002809766	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004197869	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan.

Fukuhara Y, Fuji N, Yamazaki N, Hirakiyama A, Kamioka T, Seo JH, Mashima R, Kosuga M, Okuyama T.

Mol Genet Metab Rep. 2018 Mar;14:3-9. doi: 10.1016/j.ymgmr.2017.10.009.

PubMed [citation]

PMID:: 29124014
PMCID:: PMC5671405

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000220363.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919379.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GAA c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 1.6e-05 in 244686 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.6e-05 vs 0.0042), allowing no conclusion about variant significance. The variant, c.569G>A, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001226092.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the GAA protein (p.Arg190His). This variant is present in population databases (rs528367092, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 23000108, 24444888, 29149851, 31076647). ClinVar contains an entry for this variant (Variation ID: 188809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg190 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 29046207), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422620.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

Description

The p.Arg190His variant in GAA has been reported in 2 Dutch and 1 Taiwanese individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 23000108, 24444888), and has also been reported likely pathogenic by Counsyl and pathogenic by Integrated Genetics in ClinVar (Variation ID: 188809). This variant has been identified in 0.006% (1/16218) of African chromosomes, 0.006% (2/34578) of Latino chromosomes, and 0.001% (1/113436) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs528367092). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Arg190His variant may impact GAA activity and proteolytically activated GAA levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One species (scarlet macaw) carries a Histidine (His) at this position, raising the possibility that this change at this position may be tolerated. However, the presence of this variant in combination with pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg190His variant is pathogenic (PMID: 23000108, 24444888). The phenotype of 3 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity assay results in fibroblasts or a dried blood spot (PMID: 23000108, 24444888). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PP3, PM2, PP4, PM3_Supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002809766.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004197869.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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