NM_000152.5(GAA):c.1979G>A (p.Arg660His) AND Glycogen storage disease, type II

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 9, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000169600.9

Allele description [Variation Report for NM_000152.5(GAA):c.1979G>A (p.Arg660His)]

NM_000152.5(GAA):c.1979G>A (p.Arg660His)

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.1979G>A (p.Arg660His)
HGVS:
  • NC_000017.11:g.80112966G>A
  • NG_009822.1:g.16411G>A
  • NM_000152.5:c.1979G>AMANE SELECT
  • NM_001079803.3:c.1979G>A
  • NM_001079804.3:c.1979G>A
  • NP_000143.2:p.Arg660His
  • NP_001073271.1:p.Arg660His
  • NP_001073272.1:p.Arg660His
  • LRG_673t1:c.1979G>A
  • LRG_673:g.16411G>A
  • NC_000017.10:g.78086765G>A
  • NM_000152.3:c.1979G>A
  • NM_001079803.2:c.1979G>A
  • P10253:p.Arg660His
Protein change:
R660H
Links:
UniProtKB: P10253#VAR_046477; dbSNP: rs374143224
NCBI 1000 Genomes Browser:
rs374143224
Molecular consequence:
  • NM_000152.5:c.1979G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.1979G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.1979G>A - 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
SCV000221116Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 4, 2015)
unknownliterature only

PubMed (8)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000626537Invitaecriteria provided, single submitter
Pathogenic
(Oct 9, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000894163Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

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

SCV000917390Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 9, 2018)
germlineclinical testing

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

Citation Link,

SCV001133216Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical Cityno assertion criteria providedLikely pathogenic
(Sep 26, 2019)
germlineclinical testing

SCV001459744Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing, literature only

Citations

PubMed

The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase.

Flanagan JJ, Rossi B, Tang K, Wu X, Mascioli K, Donaudy F, Tuzzi MR, Fontana F, Cubellis MV, Porto C, Benjamin E, Lockhart DJ, Valenzano KJ, Andria G, Parenti G, Do HV.

Hum Mutat. 2009 Dec;30(12):1683-92. doi: 10.1002/humu.21121.

PubMed [citation]
PMID:
19862843

Pompe disease: literature review and case series.

Dasouki M, Jawdat O, Almadhoun O, Pasnoor M, McVey AL, Abuzinadah A, Herbelin L, Barohn RJ, Dimachkie MM.

Neurol Clin. 2014 Aug;32(3):751-76, ix. doi: 10.1016/j.ncl.2014.04.010. Review.

PubMed [citation]
PMID:
25037089
PMCID:
PMC4311397
See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000221116.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (8)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000626537.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces arginine with histidine at codon 660 of the GAA protein (p.Arg660His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs374143224, ExAC 0.04%). This variant has been reported in the compound heterozygous or homozygous state in several individuals affected with Pompe disease and an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 14643388, 27649523, 20472203, 21484825, 22555271, 22521436). In addition, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Pompe disease (PMID: 20638881). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 189172). Experimental studies have shown that this missense change reduces enzyme activity to less than 10% of wild-type (PMID: 14643388). For these reasons, this variant has been classified as Pathogenic.

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

From Fulgent Genetics,Fulgent Genetics, SCV000894163.1

#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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917390.1

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

Description

Variant summary: GAA c.1979G>A (p.Arg660His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 31000 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.1979G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Pipo_2003, Bernstein_2010, Bali_2011). These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on enzyme activity (Pipo_2003, Bali_2011). The most pronounced variant effect results in <10% of normal activity. Three 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

From Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City, SCV001133216.1

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

From Natera, Inc., SCV001459744.1

#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: Oct 6, 2021

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