NM_000152.5(GAA):c.2294G>A (p.Gly765Asp) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 2, 2023
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:: RCV001345891.8

Allele description [Variation Report for NM_000152.5(GAA):c.2294G>A (p.Gly765Asp)]

NM_000152.5(GAA):c.2294G>A (p.Gly765Asp)

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.2294G>A (p.Gly765Asp)

HGVS:

NC_000017.11:g.80117072G>A
NG_009822.1:g.20517G>A
NM_000152.4:c.2294G>A
NM_000152.5:c.2294G>AMANE SELECT
NM_001079803.3:c.2294G>A
NM_001079804.3:c.2294G>A
NP_000143.2:p.Gly765Asp
NP_001073271.1:p.Gly765Asp
NP_001073272.1:p.Gly765Asp
LRG_673:g.20517G>A
NC_000017.10:g.78090871G>A
NM_000152.5:c.2294G>A

Protein change:

G765D

Links:

dbSNP: rs1292367136

NCBI 1000 Genomes Browser:

rs1292367136

Molecular consequence:

NM_000152.5:c.2294G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2294G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2294G>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
SCV001540038	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31086307, 28492532
SCV004195449	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 13, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001540038

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004195449

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 13, 2023)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease.

Kishnani PS, Gibson JB, Gambello MJ, Hillman R, Stockton DW, Kronn D, Leslie ND, Pena LDM, Tanpaiboon P, Day JW, Wang RY, Goldstein JL, An Haack K, Sparks SE, Zhao Y, Hahn SH; Pompe ADVANCE Study Consortium..

Genet Med. 2019 Nov;21(11):2543-2551. doi: 10.1038/s41436-019-0527-9. Epub 2019 May 14.

PubMed [citation]

PMID:: 31086307
PMCID:: PMC8076035

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001540038.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 765 of the GAA protein (p.Gly765Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Pompe disease (PMID: 31086307; Invitae). ClinVar contains an entry for this variant (Variation ID: 1042001). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 Baylor Genetics, SCV004195449.1

#	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

Last Updated: Sep 29, 2024

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