NM_000152.5(GAA):c.2456G>C (p.Arg819Pro) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 30, 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:: RCV002260943.2

Allele description [Variation Report for NM_000152.5(GAA):c.2456G>C (p.Arg819Pro)]

NM_000152.5(GAA):c.2456G>C (p.Arg819Pro)

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.2456G>C (p.Arg819Pro)

Other names:

NM_001079804.3:c.2456G>C

HGVS:

NC_000017.11:g.80117724G>C
NG_009822.1:g.21169G>C
NM_000152.5:c.2456G>CMANE SELECT
NM_001079803.3:c.2456G>C
NM_001079804.3:c.2456G>C
NP_000143.2:p.Arg819Pro
NP_001073271.1:p.Arg819Pro
NP_001073272.1:p.Arg819Pro
LRG_673:g.21169G>C
NC_000017.10:g.78091523G>C

Protein change:

R819P

Links:

dbSNP: rs374687883

NCBI 1000 Genomes Browser:

rs374687883

Molecular consequence:

NM_000152.5:c.2456G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2456G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2456G>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
SCV002540665	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Jun 30, 2022)	germline	curation	Citation Link,
SCV005076700	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 11, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22252923, 22644586, 30214072 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002540665

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Likely pathogenic
(Jun 30, 2022)

germline

curation

Citation Link,

SCV005076700

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 11, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience.

Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, Kishnani PS.

Am J Med Genet C Semin Med Genet. 2012 Feb 15;160C(1):40-9. doi: 10.1002/ajmg.c.31319. Epub 2012 Jan 17.

PubMed [citation]

PMID:: 22252923
PMCID:: PMC3278076

Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants.

Kroos M, Hoogeveen-Westerveld M, Michelakakis H, Pomponio R, Van der Ploeg A, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2012 Aug;33(8):1161-5. doi: 10.1002/humu.22108. Epub 2012 May 29.

PubMed [citation]

PMID:: 22644586

See all PubMed Citations (3)

Details of each submission

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002540665.1

#	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(GAA):c.2456G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 819 (p.Arg819Pro). This variant has been detected in at least 6 individuals with Pompe disease (PMID: 22644586, 22252923, 30214072) with deficient GAA activity. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and one was homozygous for the variant (PMID: 30214072, internal lab data), meeting PP4_Moderate and PM3. It is absent in gnomAD, meeting PM2. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PP4_Moderate, PM3, PS3_Moderate, PP3, PM2_Supporting, and PM5_Supporting.

#	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, SCV005076700.1

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

Description

Variant summary: GAA c.2456G>C (p.Arg819Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 31, C-terminal domain (IPR048395) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242628 control chromosomes. c.2456G>C has been reported in the literature in several individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; e.g. Bali_2012, Kazi_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Kroos_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22252923, 22644586, 30214072). ClinVar contains an entry for this variant (Variation ID: 1693550). 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

Last Updated: Jul 15, 2024

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