NM_000152.5(GAA):c.2237G>C (p.Trp746Ser) AND Glycogen storage disease, type II

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Dec 20, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000626060.5

Allele description [Variation Report for NM_000152.5(GAA):c.2237G>C (p.Trp746Ser)]

NM_000152.5(GAA):c.2237G>C (p.Trp746Ser)

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.2237G>C (p.Trp746Ser)
HGVS:
  • NC_000017.11:g.80117015G>C
  • NG_009822.1:g.20460G>C
  • NM_000152.5:c.2237G>CMANE SELECT
  • NM_001079803.2(GAA):c.2237G>C
  • NM_001079803.3:c.2237G>C
  • NM_001079804.3:c.2237G>C
  • NP_000143.2:p.Trp746Ser
  • NP_001073271.1:p.Trp746Ser
  • NP_001073272.1:p.Trp746Ser
  • LRG_673t1:c.2237G>C
  • LRG_673:g.20460G>C
  • NC_000017.10:g.78090814G>C
  • NM_000152.3:c.2237G>C
  • NM_000152.4:c.2237G>C
  • NM_001079803.2(GAA):c.2237G>C
  • NM_001079803.2:c.2237G>C
  • P10253:p.Trp746Ser
Protein change:
W746S
Links:
UniProtKB: P10253#VAR_068632; dbSNP: rs752921215
NCBI 1000 Genomes Browser:
rs752921215
Molecular consequence:
  • NM_000152.5:c.2237G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.2237G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.2237G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000746682Genomic Research Center,Shahid Beheshti University of Medical Sciencescriteria provided, single submitter
Likely pathogenic
(Dec 18, 2017)
inheritedclinical testing

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

SCV000795205Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 8, 2017)
unknownclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000950050Invitaecriteria provided, single submitter
Pathogenic
(Dec 20, 2018)
germlineclinical testing

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

SCV001422665Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedPathogenic
(Jan 22, 2020)
germlinecuration

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

Citation Link,

SCV001459753Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedinheritedunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Identification and Functional Characterization of GAA Mutations in Colombian Patients Affected by Pompe Disease.

Niño MY, Mateus HE, Fonseca DJ, Kroos MA, Ospina SY, Mejía JF, Uribe JA, Reuser AJ, Laissue P.

JIMD Rep. 2013;7:39-48. doi: 10.1007/8904_2012_138. Epub 2012 Apr 19.

PubMed [citation]
PMID:
23430493
PMCID:
PMC3575054
See all PubMed Citations (8)

Details of each submission

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV000746682.1

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

From Counsyl, SCV000795205.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000950050.1

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

Description

This sequence change replaces tryptophan with serine at codon 746 of the GAA protein (p.Trp746Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs752921215, ExAC 0.04%). This variant has been observed in several individuals affected with Pompe disease (PMID: 22081099, 18425781). ClinVar contains an entry for this variant (Variation ID: 188484). Experimental studies have shown that this missense change causes a mild disruption of GAA protein function (PMID: 23430493). This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 18458862, 21757382, 21232767, 23430493, 25526786, 27099502, 25093132), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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, SCV001422665.1

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

Description

The p.Trp746Ser variant in GAA has been reported in 1 Danish, 1 Chinese, 1 Northern European, and 6 Italian individuals with Glycogen Storage Disease II (PMID: 28490439, 24169249, 18425781, 22081099), and has been identified in 0.032% (8/24924) of African chromosomes and 0.011% (4/35424) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and Shahid Beheshti University of Medical Sciences in ClinVar (Variation ID: 188484). In vitro functional studies provide some evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant in 6 individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ser variant is pathogenic (PMID: 22081099). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in muscle tissue, consistent with disease (PMID: 22081099). Four additional variants (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) at the the same position, including a reported pathogenic variant, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 265160, 556431, 499293, 284776). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II and functional evidence. ACMG/AMP Criteria applied: PS3, PM5, PM3_supporting, PM2, PP3, PP4 (Richards 2015).

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

From Natera, Inc., SCV001459753.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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