NM_000152.5(GAA):c.755dup (p.Pro253fs) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 20, 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:: RCV000669528.4

Allele description [Variation Report for NM_000152.5(GAA):c.755dup (p.Pro253fs)]

NM_000152.5(GAA):c.755dup (p.Pro253fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.755dup (p.Pro253fs)

HGVS:

NC_000017.11:g.80107619dup
NG_009822.1:g.11064dup
NM_000152.5:c.755dupMANE SELECT
NM_001079803.3:c.755dup
NM_001079804.3:c.755dup
NP_000143.2:p.Pro253fs
NP_001073271.1:p.Pro253fs
NP_001073272.1:p.Pro253fs
LRG_673t1:c.755dup
LRG_673:g.11064dup
NC_000017.10:g.78081418dup
NM_000152.3:c.755dupT
NM_000152.5(GAA):c.755dupMANE SELECT
p.Pro253fs

Protein change:

P253fs

Links:

dbSNP: rs1555599619

NCBI 1000 Genomes Browser:

rs1555599619

Molecular consequence:

NM_000152.5:c.755dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.755dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.755dup - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000794288	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Oct 5, 2017)	unknown	clinical testing	Citation Link,
SCV001443305	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (Jul 20, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000794288

Counsyl

criteria provided, single submitter

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

Likely pathogenic
(Oct 5, 2017)

unknown

clinical testing

Citation Link,

SCV001443305

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(ClinGen LSD ACMG Specifications v1)

Pathogenic
(Jul 20, 2020)

germline

curation

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	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Counsyl, SCV000794288.1

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443305.1

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

Description

This variant, c.755dup (p.Pro253AlafsTer77), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP's specifications for PP4 and who is compound heterozygous for the variant and c.569G>A (p.Arg190His) (PMID 29124014). The phase is unknown. This is intrans data will be used in the assessment of p.Arg190His and is therefore not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 553981, one star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4.

#	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: Mar 18, 2023

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