NM_000152.5(GAA):c.1193del (p.Leu398fs) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Mar 10, 2023
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:: RCV000410060.14

Allele description [Variation Report for NM_000152.5(GAA):c.1193del (p.Leu398fs)]

NM_000152.5(GAA):c.1193del (p.Leu398fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.1193del (p.Leu398fs)

HGVS:

NC_000017.11:g.80108606del
NG_009822.1:g.12051del
NM_000152.5:c.1193delMANE SELECT
NM_001079803.3:c.1193del
NM_001079804.3:c.1193del
NP_000143.2:p.Leu398fs
NP_001073271.1:p.Leu398fs
NP_001073272.1:p.Leu398fs
LRG_673t1:c.1193del
LRG_673:g.12051del
NC_000017.10:g.78082405del
NC_000017.10:g.78082405del
NM_000152.3:c.1193delT
NM_000152.5(GAA):c.1193delMANE SELECT
p.Leu398fs

Protein change:

L398fs

Links:

dbSNP: rs1057517286

NCBI 1000 Genomes Browser:

rs1057517286

Molecular consequence:

NM_000152.5:c.1193del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.1193del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.1193del - frameshift variant - [Sequence Ontology: SO:0001589]

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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hypothetical protein (DUF295) [Arabidopsis thaliana]
hypothetical protein (DUF295) [Arabidopsis thaliana]
gi|18423799|ref|NP_568831.1|

Protein
Homo sapiens ZFP1 zinc finger protein (ZFP1), transcript variant 1, mRNA
Homo sapiens ZFP1 zinc finger protein (ZFP1), transcript variant 1, mRNA
gi|1519316104|ref|NM_153688.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000487046	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Sep 30, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000816104	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30155607, 18425781, 22252923, 28492532
SCV001443333	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Mar 10, 2023)	germline	curation	Citation Link,
SCV002799933	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 9, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004197885	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2022)	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

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.

Semplicini C, Letard P, De Antonio M, Taouagh N, Perniconi B, Bouhour F, Echaniz-Laguna A, Orlikowski D, Sacconi S, Salort-Campana E, Solé G, Zagnoli F, Hamroun D, Froissart R, Caillaud C, Laforêt P; French Pompe Study Group..

J Inherit Metab Dis. 2018 Nov;41(6):937-946. doi: 10.1007/s10545-018-0243-7. Epub 2018 Aug 28.

PubMed [citation]

PMID:: 30155607

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 (5)

Details of each submission

From Counsyl, SCV000487046.2

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

#	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 Invitae, SCV000816104.4

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

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371457). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 30155607). This sequence change creates a premature translational stop signal (p.Leu398Argfs*42) 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

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443333.2

#	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.1193del (p.Leu398ArgfsTer42) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). This variant has been reported in one patient with POmpe disease; however residual GAA activity was not provided and the second variant is not reported (PMID 30155607). There is a ClinVar entry for this variant (Variation ID: 371457). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023).

#	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, SCV002799933.1

#	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, SCV004197885.1

#	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: Feb 14, 2024

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