NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys) AND Glycogen storage disease, type II

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(2);Pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 22, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV001049848.6

Allele description [Variation Report for NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)]

NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)

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.2297A>G (p.Tyr766Cys)
HGVS:
  • NC_000017.11:g.80117075A>G
  • NG_009822.1:g.20520A>G
  • NM_000152.5:c.2297A>GMANE SELECT
  • NM_001079803.3:c.2297A>G
  • NM_001079804.3:c.2297A>G
  • NP_000143.2:p.Tyr766Cys
  • NP_001073271.1:p.Tyr766Cys
  • NP_001073272.1:p.Tyr766Cys
  • LRG_673t1:c.2297A>G
  • LRG_673:g.20520A>G
  • NC_000017.10:g.78090874A>G
  • NM_000152.3:c.2297A>G
  • NM_000152.4(GAA):c.2297A>G
  • NM_000152.4:c.2297A>G
  • P10253:p.Tyr766Cys
Protein change:
Y766C
Links:
UniProtKB: P10253#VAR_070019; dbSNP: rs144016984
NCBI 1000 Genomes Browser:
rs144016984
Molecular consequence:
  • NM_000152.5:c.2297A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.2297A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.2297A>G - 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
SCV001213921Invitaecriteria provided, single submitter
Pathogenic
(Oct 16, 2020)
germlineclinical testing

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

SCV001281478Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 28, 2017)
germlineclinical testing

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

Citation Link,

SCV001422964Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 22, 2020)
germlinecuration

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

Citation Link,

SCV001442688Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Oct 13, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001810186Nilou-Genome Labcriteria provided, single submitter
Likely pathogenic
(Jul 22, 2021)
germlineclinical testing

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

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

Clinical and Molecular Characterization of Infantile-Onset Pompe Disease in Mainland Chinese Patients: Identification of Two Common Mutations.

Chen X, Liu T, Huang M, Wu J, Zhu J, Guo Y, Xu X, Li F, Wang J, Fu L.

Genet Test Mol Biomarkers. 2017 Jun;21(6):391-396. doi: 10.1089/gtmb.2016.0424. Epub 2017 Apr 10.

PubMed [citation]
PMID:
28394184

The emerging phenotype of long-term survivors with infantile Pompe disease.

Prater SN, Banugaria SG, DeArmey SM, Botha EG, Stege EM, Case LE, Jones HN, Phornphutkul C, Wang RY, Young SP, Kishnani PS.

Genet Med. 2012 Sep;14(9):800-10. doi: 10.1038/gim.2012.44. Epub 2012 Apr 26.

PubMed [citation]
PMID:
22538254
PMCID:
PMC3947503
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV001213921.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces tyrosine with cysteine at codon 766 of the GAA protein (p.Tyr766Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs144016984, ExAC 0.006%). This variant has been observed in several individuals affected with Pompe disease (PMID: 21605996, 22538254, 30564623). ClinVar contains an entry for this variant (Variation ID: 285197). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 28394184, 22538254), 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 Illumina Clinical Services Laboratory,Illumina, SCV001281478.1

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

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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, SCV001422964.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

The p.Tyr766Cys variant in GAA has been reported in at least two individuals with glycogen storage disease II (PMID: 22676651, 21605996, 29124014) and has been identified in 0.007% (2/30610) of South Asian chromosomes and 0.004% (5/128266) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144016984). 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 in ClinVar (VariationID: 285197) as a VUS by EGL Genetics Diagnostics. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Tyr766Ser, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 420102). The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type, consistent with disease (PMID: 22676651, 21605996, 29124014). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported likely pathogenic variants c.1561G>A (VariationID: 4022; PMID: 22676651, 21605996) and p.Arg437Cys (VariationID:189082, PMID: 29124014) and in individuals with glycogen storage disease II increases the likelihood that the p.Tyr766Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM5_supporting, PP4, PM3_supporting (Richards 2015).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442688.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: GAA c.2297A>G (p.Tyr766Cys) 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 2.4e-05 in 250124 control chromosomes (gnomAD). c.2297A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. El-Gharbawy_2011, Herzog_2012, Fukuhara_2018, Nallamilli_2018). These data indicate that the variant may be associated with disease. Experimental evidence indicated GAA activity to be <10% in compound heterozygous patients with the variant (El-Gharbawy_2011, Herzog_2012, Fukuhara_2018). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and two ClinVar submitters (evaluation after 2014) cite it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Nilou-Genome Lab, SCV001810186.1

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

Last Updated: Sep 24, 2021

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