NM_000152.5(GAA):c.1316T>A (p.Met439Lys) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jun 3, 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:: RCV000410956.20

Allele description [Variation Report for NM_000152.5(GAA):c.1316T>A (p.Met439Lys)]

NM_000152.5(GAA):c.1316T>A (p.Met439Lys)

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.1316T>A (p.Met439Lys)

HGVS:

NC_000017.11:g.80108818T>A
NG_009822.1:g.12263T>A
NM_000152.5:c.1316T>AMANE SELECT
NM_001079803.3:c.1316T>A
NM_001079804.3:c.1316T>A
NP_000143.2:p.Met439Lys
NP_001073271.1:p.Met439Lys
NP_001073272.1:p.Met439Lys
LRG_673t1:c.1316T>A
LRG_673:g.12263T>A
NC_000017.10:g.78082617T>A
NM_000152.3:c.1316T>A
NM_000152.4:c.1316T>A
NM_000152.5(GAA):c.1316T>AMANE SELECT
NM_001079803.1:c.1316T>A

Protein change:

M439K

Links:

dbSNP: rs747610090

NCBI 1000 Genomes Browser:

rs747610090

Molecular consequence:

NM_000152.5:c.1316T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1316T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1316T>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
SCV000486855	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 25, 2016)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19790257, 19862843, 21471980, 20202878, 23884227 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000954422	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 9, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17092519, 20202878, 23884227, 25213570, 29124014, 19862843, 28492532
SCV001422942	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 17092519, 19862843, 28433475, 25741868 Citation Link,
SCV001983409	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 6, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17092519, 19862843, 29124014, 23884227, 34020684, 20202878, 25213570 Citation Link,
SCV002092012	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 28, 2020)	germline	clinical testing
SCV002540669	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Jun 3, 2022)	germline	curation	Citation Link,
SCV004197815	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural aspects of therapeutic enzymes to treat metabolic disorders.

Kang TS, Stevens RC.

Hum Mutat. 2009 Dec;30(12):1591-610. doi: 10.1002/humu.21111. Review.

PubMed [citation]

PMID:: 19790257

Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones.

Tajima Y, Saito S, Ohno K, Tsukimura T, Tsujino S, Sakuraba H.

J Hum Genet. 2011 Jun;56(6):440-6. doi: 10.1038/jhg.2011.36. Epub 2011 Apr 7.

PubMed [citation]

PMID:: 21471980

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000486855.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000954422.6

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

Description

ClinVar contains an entry for this variant (Variation ID: 371305). This missense change has been observed in individual(s) with Pompe disease (PMID: 17092519, 20202878, 23884227, 25213570, 29124014). This variant is present in population databases (rs747610090, gnomAD 0.04%). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 439 of the GAA protein (p.Met439Lys). 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843).

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422942.2

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

Description

The p.Met439Lys variant in GAA has been reported in 6 Korean individuals with Glycogen Storage DIsease II, segregated with disease in 2 affected siblings from 1 family (PMID: 17092519, 25213570, 28433475, 27363342), and has also been reported a pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and the Laboratory for Molecular Medicine by ClinVar (Variation ID: 371305). This variant has been identified in 0.038% (6/15644) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747610090). 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. However, the Methionine (Met) at position 439 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Met439Lys variant may impact GAA activity (PMID: 19862843). However, these types of assays may not accurately represent biological function. This variant was reported in combination with variants associated with disease and in individuals with Glycogen Storage Disease II (PMID: 25213570, 27363342, 28433475). At least one individual with this variant in the heterozygous state has a phenotype highly specific for Glycogen Storage Disease II based on GAA enzyme activity assays with leukocytes and lacks two known pseudodeficiency alleles, p.Gly576Ser and Glu689Lys, raising the likelihood that this variant is pathogenic (PMID: 28433475). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP4_Moderate (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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983409.1

#	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.1316T>A (p.Met439Lys) results in a non-conservative amino acid change located in the Glycoside hydrolase, family 31 domain (IPR000322) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 210934 control chromosomes. c.1316T>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Park_2006, Kobayashi_2010, Park_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Flanagan_2009). The most pronounced variant effect results in <2% of normal wild-type GAA activity in transiently transfected COS-7 cells. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). 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

From Natera, Inc., SCV002092012.1

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002540669.1

#	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.1316T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 439 (p.Met439Lys). At least 14 patients have been reported with this variant and features consistent with Pompe disease. This includes 7 patients with documented laboratory values showing deficiency of GAA activity, below the reference range for normal activity in leukocytes (PMIDs: 17092519, 21940687, 23884227, 25388776, 28433475, 30360039), some of whom are also reported to have histological features of Pompe disease in muscle (PMID: 20202878, 30894207), and/or documented features of infantile onset Pompe disease including muscle weakness and cardiomyoapthy (PMID: 33344388) and/or on enzyme replacement therapy (PMID: 30894207, 31193175) (PP4_Moderate). Note that pseudodeficiency variants, (p.Gly576Ser and p.Glu689Lys) were confirmed to be absent in at least one of these cases (PMID 28433475). Of these patients, 7 are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.1798C>T (p.Arg600Cys) (PMID: 20202878; phase unknown, 0.5 points), c.2238G>C (p.Trp746Cys) (PMID: 30894207, confirmed in trans, 1 point) (PMID: 25388776, unknown phase, 0.5 points), c.546G>T (PMID: 28433475, unknown phase, 0.5 points), c.2407_2413del (p.Gln803Ter) (PMID: 23884227, unknown phase, 0.5 points), and c.1579_1580del (p.Arg527GlyfsTer3) (PMID: 30360039, phase unknown, 0.5 points), and c.1225dup (PMID: 29869463; phase unknown, 0.25 points); and one patient is homozygous (PMID: 29124014) (0.5 points). Total 4.25 points (PM3_VeryStrong). Additional patients have been reported who are compound heterozygous for the variant and c.796C>T (p.Pro266Ser) (PMID: 17092519, 29044175, 31850350), c.1225dup (PMID: 29869463), and c.1309C>T (p.Arg437Cys) (PMID: 25388776) but the allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Additional data was not included due to uncertainty about the nomenclature of the second variant (PMIDs: 20202878, 21940687). The highest population minor allele frequency in gnomAD is 0.00038 (6/15644 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells the variant has <2% normal activity and does not show mature GAA protein on western blot (PMID 19862843) (PM3_Moderate). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 371305, 2 star review status) with 3 submitters classifying the variant as pathogenic and 4 as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications version 2): PM3_VeryStrong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 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, SCV004197815.2

#	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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