NM_000152.5(GAA):c.1356C>T (p.Ala452=) AND Glycogen storage disease, type II

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(2);Uncertain significance(1) (Last evaluated: Dec 4, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV001001227.6

Allele description [Variation Report for NM_000152.5(GAA):c.1356C>T (p.Ala452=)]

NM_000152.5(GAA):c.1356C>T (p.Ala452=)

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.1356C>T (p.Ala452=)
HGVS:
  • NC_000017.11:g.80109974C>T
  • NG_009822.1:g.13419C>T
  • NM_000152.5:c.1356C>TMANE SELECT
  • NM_001079803.3:c.1356C>T
  • NM_001079804.3:c.1356C>T
  • NP_000143.2:p.Ala452=
  • NP_001073271.1:p.Ala452=
  • NP_001073272.1:p.Ala452=
  • LRG_673t1:c.1356C>T
  • LRG_673:g.13419C>T
  • NC_000017.10:g.78083773C>T
  • NM_000152.3:c.1356C>T
  • NM_000152.4(GAA):c.1356C>T
  • p.Ala452=
Links:
dbSNP: rs757893858
NCBI 1000 Genomes Browser:
rs757893858
Molecular consequence:
  • NM_000152.5:c.1356C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001079803.3:c.1356C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001079804.3:c.1356C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV001043667Invitaecriteria provided, single submitter
Likely benign
(Dec 4, 2020)
germlineclinical testing

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

SCV001158390ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely benign
(May 3, 2019)
germlineclinical testing

Citation Link,

SCV001282567Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 28, 2017)
germlineclinical testing

Citation Link,

SCV001422896Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely benign
(Jan 22, 2020)
germlinecuration

Citation Link,

SCV001453426Natera, Inc.no assertion criteria providedUncertain significance
(Jan 24, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001043667.3

#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 ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001158390.1

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

From Illumina Clinical Services Laboratory,Illumina, SCV001282567.1

#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 Institute Rare Disease Group, Broad Institute, SCV001422896.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1356C>T (p.Ala452=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and Blueprint Genetics and likely benign by GeneDx in ClinVar (Variation ID: 286268). This variant has been identified in 0.014% (5/35404) of Latino chromosomes and 0.010% (13/128368) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757893858). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: PM2, BP4, BP7 (Richards 2015).

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

From Natera, Inc., SCV001453426.1

#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: May 16, 2021

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