NM_000152.5(GAA):c.743T>C (p.Leu248Pro) AND Glycogen storage disease, type II

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Aug 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001249006.5

Allele description

NM_000152.5(GAA):c.743T>C (p.Leu248Pro)

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.743T>C (p.Leu248Pro)

HGVS:

NC_000017.11:g.80107607T>C
NG_009822.1:g.11052T>C
NM_000152.5:c.743T>CMANE SELECT
NM_001079803.3:c.743T>C
NM_001079804.3:c.743T>C
NP_000143.2:p.Leu248Pro
NP_001073271.1:p.Leu248Pro
NP_001073272.1:p.Leu248Pro
LRG_673:g.11052T>C
NC_000017.10:g.78081406T>C
NM_000152.4:c.743T>C
NM_001079804.2:c.743T>C

Protein change:

L248P

Links:

dbSNP: rs1443844938

NCBI 1000 Genomes Browser:

rs1443844938

Molecular consequence:

NM_000152.5:c.743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.743T>C - 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
SCV001422852	Broad Institute Rare Disease Group, Broad Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 18425781, 25741868 Citation Link,
SCV002547864	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 31, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18425781, 29122469, 29061980, 31254424 Citation Link,
SCV002790507	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 24, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195508	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 19, 2023)	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

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease.

Mori M, Haskell G, Kazi Z, Zhu X, DeArmey SM, Goldstein JL, Bali D, Rehder C, Cirulli ET, Kishnani PS.

Mol Genet Metab. 2017 Dec;122(4):189-197. doi: 10.1016/j.ymgme.2017.10.008. Epub 2017 Oct 17.

PubMed [citation]

PMID:: 29122469
PMCID:: PMC5907499

See all PubMed Citations (5)

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001422852.2

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

Description

The p.Leu248Pro variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 18425781, 29122469), and has been identified in 0.002% (2/128914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1443844938). 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.Leu248Pro variant may impact protein function (PMID: 18425781). 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. Additionally, this variant has been reported in combination with a reported pathogenic variant in an individual with glycogen storage disease II (VariationID: 4027; PMID 29122469). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002547864.1

#	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.743T>C (p.Leu248Pro) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) 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 4e-06 in 251170 control chromosomes. c.743T>C has been reported in the literature in at-least two individuals, one of whom has a non-informative genotype (no second allele specified) (example, Kroos_2008) while the other is an adult with compound heterozygous genotype and late onset Pompe disease (example, Mori_2017). It has also been listed as having an unknown clinical severity rating in the Pompe variant database update (Nino_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro. The most pronounced variant effect results in 18% of normal acid alpha-glucosidase activity in cells while reporting 0% of normal activity in the medium (Kroos_2008). Two 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 likely pathogenic. 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 Fulgent Genetics, Fulgent Genetics, SCV002790507.1

#	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, SCV004195508.1

#	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: Mar 16, 2024

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