NM_000152.5(GAA):c.2236T>C (p.Trp746Arg) AND Glycogen storage disease, type II

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jul 30, 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:: RCV000598534.16

Allele description [Variation Report for NM_000152.5(GAA):c.2236T>C (p.Trp746Arg)]

NM_000152.5(GAA):c.2236T>C (p.Trp746Arg)

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.2236T>C (p.Trp746Arg)

HGVS:

NC_000017.11:g.80117014T>C
NG_009822.1:g.20459T>C
NM_000152.5:c.2236T>CMANE SELECT
NM_001079803.3:c.2236T>C
NM_001079804.3:c.2236T>C
NP_000143.2:p.Trp746Arg
NP_001073271.1:p.Trp746Arg
NP_001073272.1:p.Trp746Arg
LRG_673t1:c.2236T>C
LRG_673:g.20459T>C
NC_000017.10:g.78090813T>C
NM_000152.3:c.2236T>C
NM_000152.4:c.2236T>C

Protein change:

W746R

Links:

dbSNP: rs1479740763

NCBI 1000 Genomes Browser:

rs1479740763

Molecular consequence:

NM_000152.5:c.2236T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2236T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2236T>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
SCV001554637	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29122469, 23430493, 30564623, 31086307, 31254424, 33202836 Citation Link,
SCV001810183	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]
SCV002235074	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 30, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9535769, 21232767, 21757382, 25093132, 27099502, 23430493, 29122469, 28492532
SCV004197813	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 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	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease.

Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS.

Genet Med. 2011 Aug;13(8):729-36. doi: 10.1097/GIM.0b013e3182174703.

PubMed [citation]

PMID:: 21637107
PMCID:: PMC3954622

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M.

Ann Clin Transl Neurol. 2018 Dec;5(12):1574-1587. doi: 10.1002/acn3.649.

PubMed [citation]

PMID:: 30564623
PMCID:: PMC6292381

See all PubMed Citations (14)

Details of each submission

From Counsyl, SCV000800152.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	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, SCV001554637.2

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

Description

Variant summary: GAA c.2236T>C (p.Trp746Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This alters a highly conserved residue (HGMD) in which other missense variants have been found in association with disease and some have been classified as pathogenic by ClinVar submitters (e.g. p.Trp746Cys). The variant was absent in 250780 control chromosomes (gnomAD). c.2236T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; Nino_2013, Mori_2017, Nallamilli_2018, Kishnani_2019), and some were reported as compound heterozygous with a pathogenic variant. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Nino_2013), finding that the variant results in <10% of normal GAA activity. The following publications have been ascertained in the context of this evaluation (PMID: 29122469, 23430493, 30564623, 31086307, 31254424, 33202836). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=5) or uncertain significance (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 Genome-Nilou Lab, SCV001810183.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002235074.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9535769, 21232767, 21757382, 25093132, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GAA function (PMID: 23430493). ClinVar contains an entry for this variant (Variation ID: 499293). This missense change has been observed in individuals with GAA-related conditions (PMID: 23430493, 29122469). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 746 of the GAA protein (p.Trp746Arg).

#	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, SCV004197813.1

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800152	Counsyl	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 23, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23430493, 21637107 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800152

Counsyl

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(May 23, 2018)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Last Updated: Sep 29, 2024

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