NM_000152.5(GAA):c.2512C>T (p.Gln838Ter) AND Glycogen storage disease, type II

Clinical significance:Pathogenic (Last evaluated: May 4, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001200861.2

Allele description [Variation Report for NM_000152.5(GAA):c.2512C>T (p.Gln838Ter)]

NM_000152.5(GAA):c.2512C>T (p.Gln838Ter)

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.2512C>T (p.Gln838Ter)
HGVS:
  • NC_000017.11:g.80118223C>T
  • NG_009822.1:g.21668C>T
  • NM_000152.5:c.2512C>TMANE SELECT
  • NM_001079803.3:c.2512C>T
  • NM_001079804.3:c.2512C>T
  • NP_000143.2:p.Gln838Ter
  • NP_001073271.1:p.Gln838Ter
  • NP_001073272.1:p.Gln838Ter
  • LRG_673t1:c.2512C>T
  • LRG_673:g.21668C>T
  • LRG_673p1:p.Gln838*
  • NC_000017.10:g.78092022C>T
  • NM_000152.3:c.2512C>T
  • NM_000152.4(GAA):c.2512C>T
  • NM_000152.5(GAA):c.2512C>TMANE SELECT
  • NP_000143.2:p.Gln838*
  • p.Gln838Ter
Protein change:
Q838*
Links:
dbSNP: rs369532274
NCBI 1000 Genomes Browser:
rs369532274
Molecular consequence:
  • NM_000152.5:c.2512C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001079803.3:c.2512C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001079804.3:c.2512C>T - 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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001371718ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGenreviewed by expert panel
Pathogenic
(May 4, 2020)
germlinecuration

Citation Link,

SCV001422608Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedPathogenic
(Jan 22, 2020)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Immune Tolerance Strategies in Siblings with Infantile Pompe Disease-Advantages for a Preemptive Approach to High-Sustained Antibody Titers.

Stenger EO, Kazi Z, Lisi E, Gambello MJ, Kishnani P.

Mol Genet Metab Rep. 2015 Sep 1;4:30-34.

PubMed [citation]
PMID:
26167453
PMCID:
PMC4497810

Details of each submission

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen, SCV001371718.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

This variant, c.2512C>T (p.Gln838Ter), 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 0.00006 in the African population, meeting PM2. It has been reported in two siblings with infantile onset Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4, and who are compound heterozygous for the variant and c.2105G>T (p.Arg702Leu) (PMID 26167453). However, this in trans data will be used in the assessment of p.Arg702Leu and is not included here in order to avoid a circular argument. Another patient, with limb girdle muscular dystrophy, has been reported to be compound heterozygous for the variant and c.-32-13T>G. However, residual GAA activity was not provided, and therefore this data was not included (PMID 30564623). There is a ClinVar entry for this variant (Variation ID: 92479, 1 star review status) with one submitter classifying the variant as 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.

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

From Broad Institute Rare Disease Group, Broad Institute, SCV001422608.1

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

Description

The p.Gln838Ter variant in GAA has been reported in 2 African American individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 26167453), and has also been reported pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 92479). This variant has been identified in 0.006% (1/16188) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs369532274). 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 838, 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. This variant has been reported in trans with a reported likely pathogenic variant and in 2 individuals with Glycogen Storage Disease II (PMID: 26167453; Variation ID: 92472). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in fibroblasts or muscle tissue (PMID: 26167453). 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 occurrences with a reported likely pathogenic GAA variant in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).

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

Last Updated: Nov 27, 2021

Support Center