NM_000152.5(GAA):c.953T>A (p.Met318Lys) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Oct 26, 2021
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:: RCV000675007.17

Allele description [Variation Report for NM_000152.5(GAA):c.953T>A (p.Met318Lys)]

NM_000152.5(GAA):c.953T>A (p.Met318Lys)

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>A (p.Met318Lys)

Other names:

NM_000152.5(GAA):c.953T>A; p.Met318Lys

HGVS:

NC_000017.11:g.80107894T>A
NG_009822.1:g.11339T>A
NM_000152.5:c.953T>AMANE SELECT
NM_001079803.3:c.953T>A
NM_001079804.3:c.953T>A
NP_000143.2:p.Met318Lys
NP_001073271.1:p.Met318Lys
NP_001073272.1:p.Met318Lys
LRG_673t1:c.953T>A
LRG_673:g.11339T>A
NC_000017.10:g.78081693T>A
NM_000152.3:c.953T>A
NM_000152.4:c.953T>A

Protein change:

M318K

Links:

dbSNP: rs121907936

NCBI 1000 Genomes Browser:

rs121907936

Molecular consequence:

NM_000152.5:c.953T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.953T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.953T>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
SCV000800433	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 5, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18425781, 21484825, 22644586 Citation Link,
SCV001218186	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 20, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1652892, 29181627, 19862843, 29122469, 22644586, 21484825, 28492532
SCV001810540	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]
SCV002032124	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Oct 26, 2021)	germline	curation	Citation Link,
SCV002500450	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 18, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18425781, 21484825, 22644586, 30076350 Citation Link,
SCV005058753	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 28, 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	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

Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele.

Zhong N, Martiniuk F, Tzall S, Hirschhorn R.

Am J Hum Genet. 1991 Sep;49(3):635-45.

PubMed [citation]

PMID:: 1652892
PMCID:: PMC1683123

Pompe disease in Austria: clinical, genetic and epidemiological aspects.

Löscher WN, Huemer M, Stulnig TM, Simschitz P, Iglseder S, Eggers C, Moser H, Möslinger D, Freilinger M, Lagler F, Grinzinger S, Reichhardt M, Bittner RE, Schmidt WM, Lex U, Brunner-Krainz M, Quasthoff S, Wanschitz JV.

J Neurol. 2018 Jan;265(1):159-164. doi: 10.1007/s00415-017-8686-6. Epub 2017 Nov 27.

PubMed [citation]

PMID:: 29181627
PMCID:: PMC5760608

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000800433.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001218186.5

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

Description

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. This variant disrupts the p.Met318 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1652892, 29181627, 19862843, 29122469). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect GAA protein function (PMID: 22644586). This variant has been observed in combination with another GAA variant in¬† an individual affected with glycogen storage disease (PMID: 21484825). ClinVar contains an entry for this variant (Variation ID: 558700). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 318 of the GAA protein (p.Met318Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine.

#	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, SCV001810540.1

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002032124.1

#	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>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 318 (p.Met318Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was found in compound heterozygosity (phase unknown) with a unique pathogenic variant in GAA in one patient with Pompe disease (PMID: 21484825). Additional cases (PMID: 18425781) have been reported but were not included because a second variant and/or zygosity was not specified (PP4_Moderate, PM3_Supporting). Expression of the variant in COS cells resulted in 3.2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.926 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: 558700; 1 star review status) with 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021).

#	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, SCV002500450.1

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

Description

Variant summary: GAA c.953T>A (p.Met318Lys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 236242 control chromosomes (gnomAD). c.953T>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease database, Kroos_2008, Bali_2011, Sun_2018). These data indicate that the variant may be associated with disease. Kroos_2012 has shown that the variant results in 3.2% enzymatic activity in cell culture. Four ClinVar submitters, including one expert panel, have assessed the variant since 2014: three, including the expert panel, classified the variant as likely pathogenic and one as of uncertain significance. Based on the evidence outlined above, the variant was 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 Baylor Genetics, SCV005058753.1

#	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: Sep 29, 2024

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