NM_000152.5(GAA):c.953T>C (p.Met318Thr) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Sep 6, 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:: RCV000780268.18

Allele description [Variation Report for NM_000152.5(GAA):c.953T>C (p.Met318Thr)]

NM_000152.5(GAA):c.953T>C (p.Met318Thr)

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.953T>C (p.Met318Thr)

Other names:

NM_000152.5(GAA):c.953T>C

HGVS:

NC_000017.11:g.80107894T>C
NG_009822.1:g.11339T>C
NM_000152.5:c.953T>CMANE SELECT
NM_001079803.3:c.953T>C
NM_001079804.3:c.953T>C
NP_000143.2:p.Met318Thr
NP_001073271.1:p.Met318Thr
NP_001073272.1:p.Met318Thr
LRG_673t1:c.953T>C
LRG_673:g.11339T>C
NC_000017.10:g.78081693T>C
NM_000152.3:c.953T>C
NM_000152.4(GAA):c.953T>C
NM_000152.4:c.953T>C
P10253:p.Met318Thr

Protein change:

M318T; MET318THR

Links:

UniProtKB: P10253#VAR_004289; OMIM: 606800.0002; dbSNP: rs121907936

NCBI 1000 Genomes Browser:

rs121907936

Molecular consequence:

NM_000152.5:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.953T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.953T>C - 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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Gosr1 golgi SNAP receptor complex member 1 [Rattus norvegicus]
Gosr1 golgi SNAP receptor complex member 1 [Rattus norvegicus]
Gene ID:94189

Gene
94189[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000917391	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 20, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21228398, 19862843, 29122469, 1652892, 29181627, 31342611, 30214072 Citation Link,
SCV001199377	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29122469, 29181627, 1652892, 19862843, 21484825, 28492532
SCV001244231	Molecular Therapies Laboratory, Murdoch University	no assertion criteria provided	Pathogenic (Jan 7, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1652892, 32317649
SCV001423074	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 (3) [See all records that cite these PMIDs] 25139343, 1652892, 25741868 Citation Link,
SCV001810551	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059383	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 16, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002583364	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Sep 6, 2022)	germline	curation	Citation Link,
SCV004195515	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Carrier testing for severe childhood recessive diseases by next-generation sequencing.

Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J, Langley RJ, Zhang L, Lee CC, Schilkey FD, Sheth V, Woodward JE, Peckham HE, Schroth GP, Kim RW, Kingsmore SF.

Sci Transl Med. 2011 Jan 12;3(65):65ra4. doi: 10.1126/scitranslmed.3001756.

PubMed [citation]

PMID:: 21228398
PMCID:: PMC3740116

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

Reuser AJJ, van der Ploeg AT, Chien YH, Llerena J Jr, Abbott MA, Clemens PR, Kimonis VE, Leslie N, Maruti SS, Sanson BJ, Araujo R, Periquet M, Toscano A, Kishnani PS, On Behalf Of The Pompe Registry Sites.

Hum Mutat. 2019 Nov;40(11):2146-2164. doi: 10.1002/humu.23878. Epub 2019 Aug 7.

PubMed [citation]

PMID:: 31342611
PMCID:: PMC6852536

See all PubMed Citations (12)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917391.2

#	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.953T>C (p.Met318Thr) 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 allele was found at a frequency of 4.2e-05 in 236242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.2e-05 vs 0.0042), allowing no conclusion about variant significance. c.953T>C has been reported in the literature in several individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (ie. Zhong_1991, Flanagan_2009, Mori_2017, Loscher_2018, Kazi_2019). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in <10% of normal activity (Zhong_1991, Flanagan_2009). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six labs classified as likely pathogenic/pathogenic while one classified as VUS. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001199377.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 318 of the GAA protein (p.Met318Thr). This variant is present in population databases (rs121907936, gnomAD 0.009%). This missense change has been observed in individuals with Pompe disease (PMID: 1652892, 19862843, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 4021). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GAA function (PMID: 1652892, 19862843). This variant disrupts the p.Met318 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21484825), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been 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 Molecular Therapies Laboratory, Murdoch University, SCV001244231.1

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

#	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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423074.2

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

Description

The heterozygous p.Met318Thr variant in GAA has been reported in 2 individuals with Glycogen Storage Disease II (PMID: 1652892, 25139343), and has also been reported pathogenic by OMIM, likely pathogenic by Integrated Genetics, and a VUS by EGL Genetic Diagnostics in ClinVar (Variation ID: 4021). This variant has been identified in 0.009% (2/23234) of African chromosomes and 0.006% (7/121686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907936). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with a minigene assay provide some evidence that the p.Met318Thr variant may eliminate GAA activity (PMID: 1652892). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. However, the Methionine (Met) at position 318 is not conserved in evolutionary distant species, raising the possibility that a change at this position may be tolerated. Two additional variants at the same position, p.Met318Lys and p.Met318Leu, have been reported as VUS in ClinVar but p.Met318Lys is a likely pathogenic variant, slightly increasing the likelihood that the p.Met318Thr variant is pathogenic (Variation ID: 558700, 290616; PMID: 21484825, 22644586). This variant has been reported in combination with a reported likely pathogenic variant and a variant reported to cause NMD, and in individuals with Glycogen Storage Disease II (PMID: 1652892, 25139343). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM5_Supporting, PP3, 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 Genome-Nilou Lab, SCV001810551.1

#	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 Centogene AG - the Rare Disease Company, SCV002059383.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002583364.1

#	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.953T>C variant in GAA is a missense variant predicted to cause substitution of methionine by threonine at amino acid 318 (p.Met318Thr). Twelve probands with a diagnosis of Pompe disease were identified with this variant. At least 9 of them have GAA activity in the affected range in dried blood spots or <30% normal GAA activity in fibroblasts (PMIDs: 1652892, 19862843, 25139343, 30214072, 34357340, clinical laboratory data) with pseudodeficiency variants confirmed absent in three of these patients (clinical laboratory data) (PP4_Moderate). Of these patients, 10 are compound heterozygous for c.953T>C (p.Met318Thr) and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP; either c.2560C>T (p.Arg854Ter), confirmed in trans (PMID: 1652892, 19862843), c.1979G>A (p.Arg660His), confirmed in trans by parental testing (clinical diagnostic laboratory); c.-32-13T>G, phase unknown (PMIDs: 29122469, 31904026, 32317649, clinical diagnostic laboratory) (at least 5 patients, 1 confirmed in trans) c.2481+102_2646+31del (p.Gly828_Asn882del), phase unknown (clinical diagnostic laboratory), c.1292_1295dupTGCA, phase unknown (PMID: 30214072), or c.1082C>T (p.Pro361Leu), phase unknown (PMID: 25139343). One patient is homozygous for the variant (PMID: 34357340) (0.5 points) (PM3_Very Strong). Another patient is compound heterozygous for the variant and c.692+5G>T (PMID: 29181627) but the allelic data from this patient will be used in the classification of c.692+5G>T and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Suporting, and therefore meets this criterion (PM2_Supporting). Functional studies involving expression of the variant in cultured cells indicate that the variant impacts function, resulting in <2% GAA activity (PMID: 1652892, 19862843). The computational predictor REVEL gives a score of 0.89, 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: 4021; 1 star review status) with 3 submitters classifying the variant as pathogenic, two as likley pathogenic and one as a variant of uncertain significance. With data from the published literature and a clinical laboratory, we find that the 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 2.0): PM3_Very Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. Classification approved by the ClinGen LSD VCEP on Sept. 6, 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, SCV004195515.2

#	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

Relating variation to medicine