NM_000152.5(GAA):c.710C>T (p.Ala237Val) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Nov 2, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000664615.13

Allele description [Variation Report for NM_000152.5(GAA):c.710C>T (p.Ala237Val)]

NM_000152.5(GAA):c.710C>T (p.Ala237Val)

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.710C>T (p.Ala237Val)

HGVS:

NC_000017.11:g.80107574C>T
NG_009822.1:g.11019C>T
NM_000152.5:c.710C>TMANE SELECT
NM_001079803.3:c.710C>T
NM_001079804.3:c.710C>T
NP_000143.2:p.Ala237Val
NP_001073271.1:p.Ala237Val
NP_001073272.1:p.Ala237Val
LRG_673t1:c.710C>T
LRG_673:g.11019C>T
LRG_673p1:p.Ala237Val
NC_000017.10:g.78081373C>T
NC_000017.10:g.78081373C>T
NM_000152.3:c.710C>T
NM_000152.4:c.710C>T
NM_000152.5(GAA):c.710C>TMANE SELECT
P10253:p.Ala237Val

Protein change:

A237V; ALA237VAL

Links:

UniProtKB: P10253#VAR_029027; OMIM: 606800.0016; dbSNP: rs121907944

NCBI 1000 Genomes Browser:

rs121907944

Molecular consequence:

NM_000152.5:c.710C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.710C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.710C>T - 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
SCV000788610	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Apr 28, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15668445, 19862843, 17643989 Citation Link,
SCV001422612	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 (2) [See all records that cite these PMIDs] 15668445, 25741868 Citation Link,
SCV002265225	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15668445, 19862843, 31086307, 28492532
SCV002817450	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Uncertain significance (Nov 2, 2022)	germline	curation	Citation Link,
SCV005058751	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 30, 2024)	unknown	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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients.

Müller-Felber W, Horvath R, Gempel K, Podskarbi T, Shin Y, Pongratz D, Walter MC, Baethmann M, Schlotter-Weigel B, Lochmüller H, Schoser B.

Neuromuscul Disord. 2007 Oct;17(9-10):698-706. Epub 2007 Jul 23.

PubMed [citation]

PMID:: 17643989

Mutations in the acid alpha-glucosidase gene (M. Pompe) in a patient with an unusual phenotype.

Anneser JM, Pongratz DE, Podskarbi T, Shin YS, Schoser BG.

Neurology. 2005 Jan 25;64(2):368-70.

PubMed [citation]

PMID:: 15668445

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000788610.1

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

#	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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422612.2

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

Description

The heterozygous p.Ala237Val variant in GAA has been reported in 1 German individual with Glycogen Storage Disease II (PMID: 15668445), and has also been reported as a VUS by Counsyl and pathogenic by OMIM in ClinVar (Variation ID: 4035). This variant has been identified in 0.013% (4/30616) of South Asian chromosomes and 0.001% (1/113342) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907944). 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 do not provide strong support for or against an impact to the protein. The presence of this variant in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ala237Val variant is pathogenic (PMID: 15668445). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PM2, PP4 (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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002265225.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 237 of the GAA protein (p.Ala237Val). This variant is present in population databases (rs121907944, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 15668445). ClinVar contains an entry for this variant (Variation ID: 4035). 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: 19862843). This variant disrupts the p.A237G amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 31086307), which suggests that this may be a clinically significant amino acid residue. 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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002817450.1

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

Description

The NM_000152.5:c.710C>T variant in GAA is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 237 (p.Ala237Val). A patient with late onset Pompe disease and this variant has been described with a severely reduced GAA activity (<10% normal) and an increase of total glycogen in muscle (PMID: 15668445, 17573812, 17643989) (PP4_Moderate). This patient is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.877G>A (p.Gly293Arg) (PMID: 15668445, 17573812, 17643989) (PM3_Supporting). Another patient has been reported who is compound heterozygous for the variant and p.Met173del (PMID: 28196920). However, the cDNA changes for these variants were not provided and therefore the data was not included. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00013 (4/30616 alleles) in the South Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had "greater than 2% wild-type GAA activity", but the activity was not provided (PS3 not met). The computational predictor REVEL gives a score of 0.693 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP on November 2, 2022)

#	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, SCV005058751.1

#	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: Oct 13, 2024

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