NM_000152.5(GAA):c.1836C>G (p.His612Gln) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 15, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001249047.3

Allele description [Variation Report for NM_000152.5(GAA):c.1836C>G (p.His612Gln)]

NM_000152.5(GAA):c.1836C>G (p.His612Gln)

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.1836C>G (p.His612Gln)

HGVS:

NC_000017.11:g.80112659C>G
NG_009822.1:g.16104C>G
NM_000152.5:c.1836C>GMANE SELECT
NM_001079803.3:c.1836C>G
NM_001079804.3:c.1836C>G
NP_000143.2:p.His612Gln
NP_001073271.1:p.His612Gln
NP_001073272.1:p.His612Gln
LRG_673:g.16104C>G
NC_000017.10:g.78086458C>G

Protein change:

H612Q

Links:

dbSNP: rs768397968

NCBI 1000 Genomes Browser:

rs768397968

Molecular consequence:

NM_000152.5:c.1836C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1836C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1836C>G - 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
SCV001422992	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 15, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 17915575, 16917947, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422992

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 15, 2020)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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	curation

Citations

PubMed

Molecular genetics of late onset glycogen storage disease II in Italy.

Pittis MG, Filocamo M.

Acta Myol. 2007 Jul;26(1):67-71.

PubMed [citation]

PMID:: 17915575
PMCID:: PMC2949324

Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II.

Montalvo AL, Bembi B, Donnarumma M, Filocamo M, Parenti G, Rossi M, Merlini L, Buratti E, De Filippi P, Dardis A, Stroppiano M, Ciana G, Pittis MG.

Hum Mutat. 2006 Oct;27(10):999-1006.

PubMed [citation]

PMID:: 16917947

See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422992.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The p.His612Gln variant in GAA has been reported in at least one Italian individual with glycogen storage disease II (PMID: 16917947, 17915575) and has been identified in 0.007% (1/15326) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs768397968). 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 using cells transfected with the variant provide some evidence that the p.His612Gln variant may impact protein function (PMID: 16917947, 17915575). 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. This variant was reported in combination with reported pathogenic variant c.-32-13T>G and in an individual with glycogen storage disease II (VariationID: 4027, PMID: 16917947). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (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

Last Updated: Mar 30, 2024

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