NM_000152.5(GAA):c.246C>A (p.Cys82Ter) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 4, 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:: RCV002260939.3

Allele description [Variation Report for NM_000152.5(GAA):c.246C>A (p.Cys82Ter)]

NM_000152.5(GAA):c.246C>A (p.Cys82Ter)

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.246C>A (p.Cys82Ter)

Other names:

NM_001079804.3:c.246C>A

HGVS:

NC_000017.11:g.80104832C>A
NG_009822.1:g.8277C>A
NM_000152.5:c.246C>AMANE SELECT
NM_001079803.3:c.246C>A
NM_001079804.3:c.246C>A
NP_000143.2:p.Cys82Ter
NP_001073271.1:p.Cys82Ter
NP_001073272.1:p.Cys82Ter
LRG_673:g.8277C>A
NC_000017.10:g.78078631C>A
NC_000017.10:g.78078631C>A

Protein change:

C82*

Links:

dbSNP: rs749584846

NCBI 1000 Genomes Browser:

rs749584846

Molecular consequence:

NM_000152.5:c.246C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.246C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.246C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002540651	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Jan 4, 2022)	germline	curation	Citation Link,
SCV004375809	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33741225, 18425781, 22252923, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002540651

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Pathogenic
(Jan 4, 2022)

germline

curation

Citation Link,

SCV004375809

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 18, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Late onset Pompe Disease in India - Beyond the Caucasian phenotype.

Puri RD, Setia N, N V, Jagadeesh S, Nampoothiri S, Gupta N, Muranjan M, Bhat M, Girisha KM, Kabra M, Verma J, Thomas DC, Biji I, Raja J, Makkar R, Verma IC, Kishnani PS.

Neuromuscul Disord. 2021 May;31(5):431-441. doi: 10.1016/j.nmd.2021.02.013. Epub 2021 Feb 16.

PubMed [citation]

PMID:: 33741225

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

See all PubMed Citations (4)

Details of each submission

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002540651.1

#	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.246C>A (p.Cys82Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PMID: 33741225) (PP4_Moderate). In summary, this variant meets the criteria to be classified as 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): PVS1, PM2_Supporting, PP4_Moderate.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004375809.1

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1693546). This premature translational stop signal has been observed in individual(s) with GAA-related conditions (PMID: 33741225). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys82*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).

#	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: Sep 29, 2024

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