NM_000152.5(GAA):c.54C>T (p.Leu18=) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 16, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000372599.6

Allele description [Variation Report for NM_000152.5(GAA):c.54C>T (p.Leu18=)]

NM_000152.5(GAA):c.54C>T (p.Leu18=)

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.54C>T (p.Leu18=)

HGVS:

NC_000017.11:g.80104640C>T
NG_009822.1:g.8085C>T
NM_000152.5:c.54C>TMANE SELECT
NM_001079803.3:c.54C>T
NM_001079804.3:c.54C>T
NP_000143.2:p.Leu18=
NP_001073271.1:p.Leu18=
NP_001073272.1:p.Leu18=
LRG_673t1:c.54C>T
LRG_673:g.8085C>T
NC_000017.10:g.78078439C>T
NM_000152.3:c.54C>T

Links:

dbSNP: rs886053542

NCBI 1000 Genomes Browser:

rs886053542

Molecular consequence:

NM_000152.5:c.54C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001079803.3:c.54C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001079804.3:c.54C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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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Nucleotide Links for Gene (Select 100616230) (18)
Nucleotide
cysteine and glycine-rich protein 2 isoform b [Homo sapiens]
cysteine and glycine-rich protein 2 isoform b [Homo sapiens]
gi|2324737714|ref|NP_001400466.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000407253	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV003463289	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 16, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22644586, 31301153, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000407253

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV003463289

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 16, 2021)

germline

clinical testing

PubMed (3)
[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

Citations

PubMed

Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants.

Kroos M, Hoogeveen-Westerveld M, Michelakakis H, Pomponio R, Van der Ploeg A, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2012 Aug;33(8):1161-5. doi: 10.1002/humu.22108. Epub 2012 May 29.

PubMed [citation]

PMID:: 22644586

Assessment of the functional impact on the pre-mRNA splicing process of 28 nucleotide variants associated with Pompe disease in GAA exon 2 and their recovery using antisense technology.

Goina E, Musco L, Dardis A, Buratti E.

Hum Mutat. 2019 Nov;40(11):2121-2130. doi: 10.1002/humu.23867. Epub 2019 Jul 29.

PubMed [citation]

PMID:: 31301153

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000407253.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Invitae, SCV003463289.1

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

Description

This sequence change affects codon 18 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Pompe disease (PMID: 22644586). ClinVar contains an entry for this variant (Variation ID: 325773). Studies have shown that this variant results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 31301153). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Apr 9, 2023

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