NM_000152.5(GAA):c.276C>A (p.Cys92Ter) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: May 4, 2020
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:: RCV000810454.11

Allele description [Variation Report for NM_000152.5(GAA):c.276C>A (p.Cys92Ter)]

NM_000152.5(GAA):c.276C>A (p.Cys92Ter)

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.276C>A (p.Cys92Ter)

HGVS:

NC_000017.11:g.80104862C>A
NG_009822.1:g.8307C>A
NM_000152.5:c.276C>AMANE SELECT
NM_001079803.3:c.276C>A
NM_001079804.3:c.276C>A
NP_000143.2:p.Cys92Ter
NP_001073271.1:p.Cys92Ter
NP_001073272.1:p.Cys92Ter
LRG_673t1:c.276C>A
LRG_673:g.8307C>A
NC_000017.10:g.78078661C>A
NC_000017.10:g.78078661C>A
NM_000152.3:c.276C>A
NM_000152.5(GAA):c.276C>AMANE SELECT
p.Cys92Ter

Protein change:

C92*

Links:

dbSNP: rs1232001857

NCBI 1000 Genomes Browser:

rs1232001857

Molecular consequence:

NM_000152.5:c.276C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.276C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.276C>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

Recent activity

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GA-binding protein alpha chain [Homo sapiens]
GA-binding protein alpha chain [Homo sapiens]
gi|34452721|ref|NP_002031.2|

Protein
Klebsiella variicola strain JNQH579 plasmid pJNQH579-1, complete sequence
Klebsiella variicola strain JNQH579 plasmid pJNQH579-1, complete sequence
gi|2067486776|gb|CP078147.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000950653	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18425781, 22252923, 28492532
SCV001371770	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Likely pathogenic (May 4, 2020)	germline	curation	Citation Link,
SCV002810305	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004197847	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000950653.4

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

Description

This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 654482). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This sequence change creates a premature translational stop signal (p.Cys92*) 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). 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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001371770.1

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

Description

This variant, c.276C>A (p.Cys92Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. This variant is absent in gnomAD v2.1.1, meeting PM2. To our knowledge, this variant has not been reported in individuals with Pompe disease in the literature and functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 654482, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2.

#	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, SCV002810305.1

#	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, SCV004197847.1

#	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: Sep 29, 2024

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