NM_000152.5(GAA):c.1317GAT[1] (p.Met440del) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 3, 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:: RCV000631056.12

Allele description [Variation Report for NM_000152.5(GAA):c.1317GAT[1] (p.Met440del)]

NM_000152.5(GAA):c.1317GAT[1] (p.Met440del)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.1317GAT[1] (p.Met440del)

Other names:

NM_000152.5(GAA):c.1317GAT[1]; p.Met440del

HGVS:

NC_000017.10:g.78082616_78082618del
NC_000017.11:g.80108819GAT[1]
NG_009822.1:g.12264GAT[1]
NM_000152.5:c.1317GAT[1]MANE SELECT
NM_001079803.3:c.1317GAT[1]
NM_001079804.3:c.1317GAT[1]
NP_000143.2:p.Met440del
NP_001073271.1:p.Met440del
NP_001073272.1:p.Met440del
LRG_673t1:c.1320_1322del
LRG_673:g.12264GAT[1]
NC_000017.10:g.78082616_78082618del
NC_000017.10:g.78082616_78082618delATG
NC_000017.10:g.78082618GAT[1]
NC_000017.11:g.80108819GAT[1]
NM_000152.3:c.1320_1322del
NM_000152.3:c.1320_1322delGAT
NM_000152.5:c.1320_1322delGATMANE SELECT

Protein change:

M440del

Links:

dbSNP: rs1555600235

NCBI 1000 Genomes Browser:

rs1555600235

Molecular consequence:

NM_000152.5:c.1317GAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001079803.3:c.1317GAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001079804.3:c.1317GAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000752046	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 1, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25526786, 28394184, 28492532
SCV001455610	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002817447	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Uncertain significance (Nov 3, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752046

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 1, 2019)

germline

clinical testing

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

SCV001455610

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

SCV002817447

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Uncertain significance
(Nov 3, 2022)

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	clinical testing, curation

Citations

PubMed

Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation.

Liu X, Wang Z, Jin W, Lv H, Zhang W, Que C, Huang Y, Yuan Y.

BMC Med Genet. 2014 Dec 20;15:141. doi: 10.1186/s12881-014-0141-2.

PubMed [citation]

PMID:: 25526786
PMCID:: PMC4411720

Clinical and Molecular Characterization of Infantile-Onset Pompe Disease in Mainland Chinese Patients: Identification of Two Common Mutations.

Chen X, Liu T, Huang M, Wu J, Zhu J, Guo Y, Xu X, Li F, Wang J, Fu L.

Genet Test Mol Biomarkers. 2017 Jun;21(6):391-396. doi: 10.1089/gtmb.2016.0424. Epub 2017 Apr 10.

PubMed [citation]

PMID:: 28394184

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752046.7

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with Pompe disease (PMID: 25526786, 28394184, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1315_1317delATG in the literature. ClinVar contains an entry for this variant (Variation ID: 526518). This variant is not present in population databases (ExAC no frequency). This variant, c.1320_1322del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Met440del), but otherwise preserves the integrity of the reading frame.

#	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 Natera, Inc., SCV001455610.1

#	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	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, SCV002817447.1

#	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.1317delGAT or c.1320_1322delGAT variant is predicted to cause a change in the length of protein due to inframe deletion of one amino acid, Met440 in a non repeat region (PM4_Supporting). This variant is documented in NBS-Pompe program from Japan (PMID: 31076647). One LOPD patient from China was reported to be compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.2238G>C (p.Trp746Cys)(PM3_supporting). This patient had documented deficiency of GAA activity (PMID: 35071497) (PP4_moderate). The variant is absent in gnomAD v2.1.1 (PM2_supporting). The results of in silico predictors were conflicting. To our knowledge, no functional studies have been performed on this variant. There is a ClinVar entry for this variant (Variant ID: 526518). Due to insufficient evidence this variant is classified as of uncertain significance for Pompe disease based on ACMG/AMP criteria applied, as specified by LSD VCEP (specification version 2.0). Criteria applied: criteria: PM2_supporting; PM3_supporting, PM4_Supporting, PP4_moderate. (Classification approved by the ClinGen LSD VCEP on Nov 3, 2022).

#	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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