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NM_000152.5(GAA):c.1265G>A (p.Arg422Gln) AND Glycogen storage disease, type II

Germline classification:
Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:
Jan 27, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV001080632.23

Allele description [Variation Report for NM_000152.5(GAA):c.1265G>A (p.Arg422Gln)]

NM_000152.5(GAA):c.1265G>A (p.Arg422Gln)

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.1265G>A (p.Arg422Gln)
HGVS:
  • NC_000017.11:g.80108767G>A
  • NG_009822.1:g.12212G>A
  • NM_000152.5:c.1265G>AMANE SELECT
  • NM_001079803.3:c.1265G>A
  • NM_001079804.3:c.1265G>A
  • NP_000143.2:p.Arg422Gln
  • NP_001073271.1:p.Arg422Gln
  • NP_001073272.1:p.Arg422Gln
  • LRG_673t1:c.1265G>A
  • LRG_673:g.12212G>A
  • NC_000017.10:g.78082566G>A
  • NM_000152.3:c.1265G>A
  • NM_000152.4(GAA):c.1265G>A
  • NM_001079803.1:c.1265G>A
  • p.Arg422Gln
Protein change:
R422Q
Links:
dbSNP: rs2229224
NCBI 1000 Genomes Browser:
rs2229224
Molecular consequence:
  • NM_000152.5:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.1265G>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
SCV000626499Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely benign
(Jan 27, 2024)
germlineclinical testing

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

SCV001281354Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Apr 27, 2017)
germlineclinical testing

Citation Link,

SCV001423077Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 22, 2020)
germlinecuration

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

Citation Link,

SCV001810597Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 22, 2021)
germlineclinical testing

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

SCV002092004Natera, Inc.
no assertion criteria provided
Likely benign
(Feb 24, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626499.9

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

From Illumina Laboratory Services, Illumina, SCV001281354.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423077.2

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

Description

The c.1265G>A variant in GAA has not been previously reported in the literature in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL and a likely benign variant by Invitae in ClinVar (Variation ID: 284246). This variant has been identified in 0.335% (65/19404) of East Asian chromosomes, 0.007% (2/29876) of South Asian chromosomes, and 0.004% (1/23700) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2229224). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One additional variant at the the same position, p.Arg422Trp, has been reported a VUS by EGL and likely benign by Invitae in ClinVar (Variation ID: 456371). In summary, while the clinical significance of the c.1265G>A variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4 (Richards 2015).

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

From Genome-Nilou Lab, SCV001810597.1

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

From Natera, Inc., SCV002092004.1

#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