NM_000152.5(GAA):c.923A>C (p.His308Pro) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 21, 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:: RCV001984443.5

Allele description [Variation Report for NM_000152.5(GAA):c.923A>C (p.His308Pro)]

NM_000152.5(GAA):c.923A>C (p.His308Pro)

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.923A>C (p.His308Pro)

HGVS:

NC_000017.11:g.80107864A>C
NG_009822.1:g.11309A>C
NM_000152.5:c.923A>CMANE SELECT
NM_001079803.3:c.923A>C
NM_001079804.3:c.923A>C
NP_000143.2:p.His308Pro
NP_001073271.1:p.His308Pro
NP_001073272.1:p.His308Pro
LRG_673:g.11309A>C
NC_000017.10:g.78081663A>C
NM_000152.4:c.923A>C

Protein change:

H308P

Links:

dbSNP: rs2143849751

NCBI 1000 Genomes Browser:

rs2143849751

Molecular consequence:

NM_000152.5:c.923A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.923A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.923A>C - 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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PREDICTED: Apis mellifera ATP-dependent RNA helicase DDX42 (LOC551822), transcri...
PREDICTED: Apis mellifera ATP-dependent RNA helicase DDX42 (LOC551822), transcript variant X2, mRNA
gi|1477730406|ref|XM_006557846.3|

Nucleotide
dae06c06.y1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4633331 5' similar to ...
dae06c06.y1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4633331 5' similar to SW:ACDB_RAT P70584 ACYL-COA DEHYDROGENASE, SHORT/BRANCHED CHAIN SPECIFIC PRECURSOR, mRNA sequence
gi|13483858|gnl|dbEST|8224414|gb|BG 1.1|

Nucleotide
dae11a07.y1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4633644 5' similar to ...
dae11a07.y1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4633644 5' similar to SW:ACTB_HUMAN P02570 ACTIN, CYTOPLASMIC 1, mRNA sequence
gi|14016209|gnl|dbEST|8495928|gb|BG 4.1|

Nucleotide
dae06h07.x1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4633573 3' similar to ...
dae06h07.x1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4633573 3' similar to SW:FA9_BOVIN P00741 COAGULATION FACTOR IX, mRNA sequence
gi|13485195|gnl|dbEST|8225751|gb|BG 8.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002279354	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 11, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19862843, 14695532, 28624228, 31086307, 28492532
SCV002600624	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 21, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22252923, 14695532, 19862843, 31086307, 27189384, 31254424, 32248831 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002279354

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 11, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002600624

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 21, 2022)

germline

clinical testing

PubMed (7)
[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	clinical testing

Citations

PubMed

Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease.

van der Wal E, Bergsma AJ, Pijnenburg JM, van der Ploeg AT, Pijnappel WWMP.

Mol Ther Nucleic Acids. 2017 Jun 16;7:90-100. doi: 10.1016/j.omtn.2017.03.001. Epub 2017 Mar 14.

PubMed [citation]

PMID:: 28624228
PMCID:: PMC5415969

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 (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002279354.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

ClinVar contains an entry for this variant (Variation ID: 1493530). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 308 of the GAA protein (p.His308Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 28624228, 31086307). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His308 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600624.1

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

Description

Variant summary: GAA c.923A>C (p.His308Pro) results in a non-conservative amino acid change located in the glycoside hydrolase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244682 control chromosomes (gnomAD). c.923A>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Bali_2012, van Capelle_2016, Vanherpe_2020). These data indicate that the variant is likely to be associated with disease. Publications reporting experimental evidence evaluating an impact on protein function found that the variant effect results in <2% of normal activity (e.g. Hermans_2004, Flanagan_2009). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. 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

Last Updated: Sep 29, 2024

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