NM_000152.5(GAA):c.871C>T (p.Leu291Phe) AND Glycogen storage disease, type II

Germline classification:: 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:: RCV001228970.16

Allele description [Variation Report for NM_000152.5(GAA):c.871C>T (p.Leu291Phe)]

NM_000152.5(GAA):c.871C>T (p.Leu291Phe)

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.871C>T (p.Leu291Phe)

Other names:

NM_000152.5(GAA):c.871C>T; p.Leu291Phe

HGVS:

NC_000017.11:g.80107812C>T
NG_009822.1:g.11257C>T
NM_000152.5:c.871C>TMANE SELECT
NM_001079803.3:c.871C>T
NM_001079804.3:c.871C>T
NP_000143.2:p.Leu291Phe
NP_001073271.1:p.Leu291Phe
NP_001073272.1:p.Leu291Phe
LRG_673t1:c.871C>T
LRG_673:g.11257C>T
NC_000017.10:g.78081611C>T
NM_000152.3:c.871C>T
NM_000152.4:c.871C>T

Protein change:

L291F

Links:

dbSNP: rs773417785

NCBI 1000 Genomes Browser:

rs773417785

Molecular consequence:

NM_000152.5:c.871C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.871C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.871C>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
SCV001401400	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 26, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25213570, 22644586, 18425781, 25526786, 30737479, 31086307, 28492532
SCV001422851	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002032133	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Oct 26, 2021)	germline	curation	Citation Link,
SCV002103372	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 21, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18425781, 25526786, 22644586, 31086307, 30737479 Citation Link,
SCV002813046	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195489	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 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

Hypertrophic cardiomyopathy in pompe disease is not limited to the classic infantile-onset phenotype.

Lee DH, Qiu WJ, Lee J, Chien YH, Hwu WL.

JIMD Rep. 2014;17:71-5. doi: 10.1007/8904_2014_339. Epub 2014 Sep 12.

PubMed [citation]

PMID:: 25213570
PMCID:: PMC4241200

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 (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001401400.5

#	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: 956209). This variant disrupts the p.Leu291 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 25213570), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). 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) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 25526786, 30737479, 31086307; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs773417785, gnomAD 0.007%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 291 of the GAA protein (p.Leu291Phe). 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422851.2

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

Description

The p.Leu291Phe variant in GAA has been reported in 3 individuals with glycogen storage disease II (PMID: 30737479, 25526786, 18425781), and has been identified in 0.006% (1/15678) of African chromosomes and 0.006% (7/110146) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773417785). 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 using COS cells transfected with the variant provide some evidence that the p.Leu291Phe variant may impact protein function (PMID: 22644586). 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. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on the absence of any known pseudodeficiency alleles and GAA enzyme activity in lymphocytes being <10% of wild type, consistent with disease (PMID: 30737479). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Leu291Pro and p.Leu291His, have been reported in association with disease in the literature (PMID: 18458862, 22644586, 18425781). Additionally, the homozygous occurrence of this variant (PMID: 30737479), as well as the presence of this variant in combination with reported pathogenic variant p.Trp746Cys (VariationID: 265160; PMID 25526786), in individuals with glycogen storage disease II increases the likelihood that the p.Leu291Phe variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on in vitro functional studies, a patient with a phenotype highly specific for the disease, the presence of other pathogenic variants at the same location, and homozygous occurrence in an affected individual with another pathogenic variant. ACMG/AMP Criteria applied: PS3, PM2, PM3_supporting, PP4_moderate, PP3 (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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002032133.1

#	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.871C>T variant in GAA is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 291 (p.Leu291Phe). Five patients with Pompe disease and this variant have been reported, four with characteristics specific for Pompe disease including published laboratory values showing deficient GAA activity and/or on enzyme replacement therapy and/or with documented symptoms consistent with infantile onset Pompe disease (PMID 25526786, 30737479, 31086307, 32849613) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown, including c.716delT (PMID 32849613; 0.5 points), c.1798C>T (p.Arg600Cys)(PMID 26253708; 0.5 points), c.2238G>C (p.Trp746Cys)(PMID 25526786; 0.5 points), and c.2481+102_2646+31del (PMID 31086307; 0.5 points). One patient who is homozygous for the variant, due to uniparental disomy, has also been reported (PMID 30737479; 0.5 points). Total 2.5 points (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006378 in the African 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 <5% wild type GAA activity and showed evidence of abnormal synthesis and processing on Western blot (PMID 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.701 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other missense changes, c.872T>C (p.Leu291Pro) and c.872T>A (p.Leu291His), at the same amino acid residue have been reported; c.872T>C (p.Leu291Pro) has been classified as pathogenic based on the specifications of the ClinGen LSD VCEP (CAID: CA401363854)(PM5). The data for this variant, c.871C>T (p.Leu291Phe, will be used in the assessment of p.Leu291His and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID 956209; 1 star review status) with two submitters classifying the variant as 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 2.0): PM5, PP3, PS3_Moderate, PM3_Strong, PM2_Supporting, PP4_Moderate. (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, SCV002103372.1

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

Description

Variant summary: GAA c.871C>T (p.Leu291Phe) 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 3.3e-05 in 245142 control chromosomes. c.871C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Kroos_2008, Liu_2014, Kishnani_2019, Labrijn-Marks_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal acid alpha-glucosidase activity (example, Kroos_2012). Three clinical diagnostic laboratories and an expert panel (ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=3; VUS, n=1). 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 Fulgent Genetics, Fulgent Genetics, SCV002813046.1

#	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

From Baylor Genetics, SCV004195489.2

#	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

ClinVar

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