NM_000152.5(GAA):c.197G>A (p.Arg66Gln) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jul 27, 2022
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:: RCV000342526.18

Allele description [Variation Report for NM_000152.5(GAA):c.197G>A (p.Arg66Gln)]

NM_000152.5(GAA):c.197G>A (p.Arg66Gln)

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.197G>A (p.Arg66Gln)

HGVS:

NC_000017.11:g.80104783G>A
NG_009822.1:g.8228G>A
NM_000152.5:c.197G>AMANE SELECT
NM_001079803.3:c.197G>A
NM_001079804.3:c.197G>A
NP_000143.2:p.Arg66Gln
NP_001073271.1:p.Arg66Gln
NP_001073272.1:p.Arg66Gln
LRG_673t1:c.197G>A
LRG_673:g.8228G>A
NC_000017.10:g.78078582G>A
NM_000152.3:c.197G>A
NM_000152.4(GAA):c.197G>A
p.Arg66Gln

Protein change:

R66Q

Links:

dbSNP: rs200202628

NCBI 1000 Genomes Browser:

rs200202628

Molecular consequence:

NM_000152.5:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.197G>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

Recent activity

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RecName: Full=C-type lectin domain family 11 member A; AltName: Full=C-type lect...
RecName: Full=C-type lectin domain family 11 member A; AltName: Full=C-type lectin superfamily member 3; AltName: Full=Lymphocyte secreted C-type lectin; AltName: Full=Osteolectin; AltName: Full=Stem cell growth factor; AltName: Full=p47; Flags: Precursor
gi|34223087|sp|Q9Y240.1|CLC11_HUMAN

Protein
RecName: Full=Epsin-1; AltName: Full=EH domain-binding mitotic phosphoprotein; A...
RecName: Full=Epsin-1; AltName: Full=EH domain-binding mitotic phosphoprotein; AltName: Full=EPS-15-interacting protein 1
gi|332278179|sp|Q9Y6I3.2|EPN1_HUMAN

Protein
AKAP10 [Mauremys mutica]
AKAP10 [Mauremys mutica]
Gene ID:123353091

Gene
AKAP10 [Calypte anna]
AKAP10 [Calypte anna]
Gene ID:103529704

Gene
PCYB_071700 [Plasmodium cynomolgi strain B]
PCYB_071700 [Plasmodium cynomolgi strain B]
Gene ID:14692016

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000407255	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Uncertain significance (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000626538	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001422668	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001463468	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jan 24, 2020)	germline	clinical testing
SCV001810174	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 22, 2021)	germline	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000407255.2

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

#	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, SCV000626538.7

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the GAA protein (p.Arg66Gln). This variant is present in population databases (rs200202628, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 325775). 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 not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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, SCV001422668.2

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

Description

The p.Arg66Gln variant in GAA has not been previously reported in the literature in individuals with Glycogen Storage Disease II but has been reported as a VUS by Invitae and Illumina and a likely benign variant by GeneDx in ClinVar (Variation ID: 325775). This variant has been identified in 0.020% (4/19680) of East Asian chromosomes, 0.014% (5/35104) of Latino chromosomes, and 0.002% (2/125336) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200202628). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The Arginine (Arg) at position 66 is not highly conserved in mammals and evolutionary distant species, and 33 species (including Gibbon, Baboon, Rhesus, Prairie Vole, and Chinchilla) carry an Glutamine (Gln), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.Arg66Gln variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (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 Natera, Inc., SCV001463468.1

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

#	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 Genome-Nilou Lab, SCV001810174.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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