NM_000152.5(GAA):c.794G>A (p.Ser265Asn) AND Glycogen storage disease, type II

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Apr 19, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000631094.12

Allele description [Variation Report for NM_000152.5(GAA):c.794G>A (p.Ser265Asn)]

NM_000152.5(GAA):c.794G>A (p.Ser265Asn)

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.794G>A (p.Ser265Asn)

Other names:

p.Ser794Asn

HGVS:

NC_000017.11:g.80107658G>A
NG_009822.1:g.11103G>A
NM_000152.5:c.794G>AMANE SELECT
NM_001079803.3:c.794G>A
NM_001079804.3:c.794G>A
NP_000143.2:p.Ser265Asn
NP_001073271.1:p.Ser265Asn
NP_001073272.1:p.Ser265Asn
LRG_673t1:c.794G>A
LRG_673:g.11103G>A
NC_000017.10:g.78081457G>A
NM_000152.3:c.794G>A
NM_000152.5:c.794G>A

Protein change:

S265N

Links:

dbSNP: rs772002851

NCBI 1000 Genomes Browser:

rs772002851

Molecular consequence:

NM_000152.5:c.794G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.794G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.794G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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LOC4344380 [Oryza sativa Japonica Group]
LOC4344380 [Oryza sativa Japonica Group]
Gene ID:4344380

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752087	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34864681, 28492532
SCV001837639	Suma Genomics, Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002027238	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002091963	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 16, 2021)	germline	clinical testing
SCV004849366	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 19, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	yes	1	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
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes.

Chawla T, Preethish-Kumar V, Polavarapu K, Vengalil S, Bardhan M, Puri R, Verma J, Christopher R, Supriya M, Nashi S, Prasad C, Nadeesh B, Nalini A.

J Neuromuscul Dis. 2022;9(2):261-273. doi: 10.3233/JND-210728.

PubMed [citation]

PMID:: 34864681

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, SCV000752087.4

#	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 serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 265 of the GAA protein (p.Ser265Asn). This variant is present in population databases (rs772002851, gnomAD 0.02%). This missense change has been observed in individual(s) with Pompe disease (PMID: 34864681). ClinVar contains an entry for this variant (Variation ID: 498281). 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 Suma Genomics, Suma Genomics, SCV001837639.1

#	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	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002027238.1

#	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

From Natera, Inc., SCV002091963.1

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV004849366.1

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

Description

A compound heterozygous variant in exon 4 of the GAA gene that results in the amino acid substitution of Aspargine for Serine at codon 265 was detected. The observed variant c.794G>A (p.Ser265Asn) has not been reported in the 1000 genomes and has MAF of 0.0024% in gnomAD databases. The in silico prediction of the variant is damaging by DANN. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.

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

Last Updated: Oct 8, 2024

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