NM_000152.5(GAA):c.2214G>A (p.Trp738Ter) AND Glycogen storage disease, type II

Clinical significance:Pathogenic (Last evaluated: Oct 5, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000409827.6

Allele description [Variation Report for NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)]

NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)

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.2214G>A (p.Trp738Ter)
HGVS:
  • NC_000017.11:g.80116992G>A
  • NG_009822.1:g.20437G>A
  • NM_000152.5:c.2214G>AMANE SELECT
  • NM_001079803.3:c.2214G>A
  • NM_001079804.3:c.2214G>A
  • NP_000143.2:p.Trp738Ter
  • NP_001073271.1:p.Trp738Ter
  • NP_001073272.1:p.Trp738Ter
  • LRG_673t1:c.2214G>A
  • LRG_673:g.20437G>A
  • NC_000017.10:g.78090791G>A
  • NM_000152.3:c.2214G>A
  • NM_000152.4(GAA):c.2214G>A
  • NM_000152.4:c.2214G>A
  • NM_000152.5(GAA):c.2214G>AMANE SELECT
  • p.Trp738Ter
Protein change:
W738*
Links:
dbSNP: rs1057516328
NCBI 1000 Genomes Browser:
rs1057516328
Molecular consequence:
  • NM_000152.5:c.2214G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001079803.3:c.2214G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001079804.3:c.2214G>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000485477Counsylcriteria provided, single submitter
Likely pathogenic
(Dec 15, 2015)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV001211539Invitaecriteria provided, single submitter
Pathogenic
(Oct 7, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001422610Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedPathogenic
(Jan 22, 2020)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001443322ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGenreviewed by expert panel
Pathogenic
(Oct 5, 2020)
germlinecuration

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002015051Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 25, 2021)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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 (8)

Details of each submission

From Counsyl, SCV000485477.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001211539.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Trp738*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with glycogen storage disease (PMID: 22676651). ClinVar contains an entry for this variant (Variation ID: 370223). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Broad Institute Rare Disease Group, Broad Institute, SCV001422610.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The p.Trp738Ter variant in GAA has been reported in 2 Chinese and 2 German individuals with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 21644219, 22676651), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370223). This variant has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516328). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 738, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a pathogenic variant, and in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Trp738Ter variant is pathogenic (PMID: 22676651). The phenotype of an individual compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity less than 10% of WT, consistent with disease (PMID: 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4, PM2 (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen, SCV001443322.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (5)

Description

This variant, c.2214G>A (p.Trp738Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, meeting PM2. An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). This data meets PM3_Supporting. In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). There is a ClinVar entry for this variant (Variation ID: 370223; 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002015051.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: GAA c.2214G>A (p.Trp738X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250908 control chromosomes. c.2214G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; Herzog_2012, Zheng_2011, Plockinger_2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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