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NM_000152.5(GAA):c.221G>A (p.Arg74His) AND Glycogen storage disease, type II

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jun 1, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001242349.6

Allele description [Variation Report for NM_000152.5(GAA):c.221G>A (p.Arg74His)]

NM_000152.5(GAA):c.221G>A (p.Arg74His)

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.221G>A (p.Arg74His)
HGVS:
  • NC_000017.11:g.80104807G>A
  • NG_009822.1:g.8252G>A
  • NM_000152.5:c.221G>AMANE SELECT
  • NM_001079803.3:c.221G>A
  • NM_001079804.3:c.221G>A
  • NP_000143.2:p.Arg74His
  • NP_001073271.1:p.Arg74His
  • NP_001073272.1:p.Arg74His
  • LRG_673t1:c.221G>A
  • LRG_673:g.8252G>A
  • NC_000017.10:g.78078606G>A
  • NM_000152.3:c.221G>A
Protein change:
R74H
Links:
dbSNP: rs764797280
NCBI 1000 Genomes Browser:
rs764797280
Molecular consequence:
  • NM_000152.5:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.221G>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001415430Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jun 1, 2022) 		germlineclinical testing

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

SCV002091893Natera, Inc.
no assertion criteria provided
Uncertain significance
(Jan 21, 2020) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001415430.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 74 of the GAA protein (p.Arg74His). This variant is present in population databases (rs764797280, gnomAD 0.03%). This missense change has been observed in individual(s) with Pompe disease (PMID: 22644586). ClinVar contains an entry for this variant (Variation ID: 967437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function. 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.

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

From Natera, Inc., SCV002091893.1

#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: Sep 29, 2024