NM_000152.5(GAA):c.2501_2502del (p.Thr834fs) AND Glycogen storage disease, type II

Clinical significance:Pathogenic (Last evaluated: May 5, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000285320.9

Allele description [Variation Report for NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)]

NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)

Gene:
GAA:alpha glucosidase [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
17q25.3
Genomic location:
Preferred name:
NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)
HGVS:
  • NC_000017.11:g.80118210CA[1]
  • NG_009822.1:g.21655CA[1]
  • NM_000152.3(GAA):c.2501_2502delCA
  • NM_000152.5:c.2501_2502delMANE SELECT
  • NM_001079803.3:c.2501_2502del
  • NM_001079804.3:c.2501_2502del
  • NP_000143.2:p.Thr834fs
  • NP_001073271.1:p.Thr834fs
  • NP_001073272.1:p.Thr834fs
  • LRG_673t1:c.2501_2502del
  • LRG_673:g.21655CA[1]
  • NC_000017.10:g.78092009CA[1]
  • NC_000017.10:g.78092009_78092010del
  • NC_000017.11:g.80118212_80118213delCA
  • NM_000152.3(GAA):c.2501_2502delCA
  • NM_000152.3:c.2501_2502del
  • NM_000152.3:c.2501_2502delCA
  • NM_000152.5:c.2501_2502delCAMANE SELECT
  • p.Thr834Argfs
Protein change:
T834fs
Links:
dbSNP: rs886043343
NCBI 1000 Genomes Browser:
rs886043343
Molecular consequence:
  • NM_000152.5:c.2501_2502del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001079803.3:c.2501_2502del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001079804.3:c.2501_2502del - frameshift variant - [Sequence Ontology: SO:0001589]
Functional consequence:
RNA degradation by nonsense-mediated decay [Variation Ontology: 0347]
Observations:
1

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
SCV000692564Tehran Medical Genetics Laboratorycriteria provided, single submitter
Likely pathogenicinheritedclinical testing

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

SCV000917399Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Nov 30, 2018)
germlineclinical testing

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

Citation Link,

SCV001132394Counsylno assertion criteria providedPathogenic
(Nov 17, 2016)
unknownclinical testing

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

SCV001371719ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGenreviewed by expert panel
Pathogenic
(May 5, 2020)
germlinecuration

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

Citation Link,

SCV001379737Invitaecriteria provided, single submitter
Pathogenic
(Jun 17, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001423058Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedPathogenic
(Jan 22, 2020)
germlinecuration

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

Citation Link,

SCV001463862Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
Iranian inheritedno1not providednot providednot providednot providedclinical testing

Citations

PubMed

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

Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients.

Palermo AT, Palmer RE, So KS, Oba-Shinjo SM, Zhang M, Richards B, Madhiwalla ST, Finn PF, Hasegawa A, Ciociola KM, Pescatori M, McVie-Wylie AJ, Mattaliano RJ, Madden SL, Marie SK, Klinger KW, Pomponio RJ.

Mol Genet Metab. 2012 Jul;106(3):287-300. doi: 10.1016/j.ymgme.2012.05.004. Epub 2012 May 14.

PubMed [citation]
PMID:
22658377
See all PubMed Citations (10)

Details of each submission

From Tehran Medical Genetics Laboratory, SCV000692564.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Iranian1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritednonot providednot providednot provided1not providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917399.1

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

Description

Variant summary: GAA c.2501_2502delCA (p.Thr834ArgfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2544delC, p.Lys849fsX38 and c.2560C>T, p.Arg854X). The variant allele was found at a frequency of 8.1e-06 in 245500 control chromosomes (gnomAD). The variant, c.2501_2502delCA, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2008, Palermo_2012, Musumeci_2012). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as 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 Counsyl, SCV001132394.1

#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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen, SCV001371719.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

This variant, c.2501_2502delCA (p.Thr834Argfs) is predicted to result in a frameshift causing a premature termination codon, nonsense medicated decay, and lack of GAA gene product, meeting PVS1. The variant has a highest population minor allele frequency of 0.00005794 in the Latino population, meeting PM2. This variant was found in compound heterozygosity with a known pathogenic variant, c.-32-13T>G, in three patients, who all meet the ClinGen LSD VCEP's PP4 criterion (PMID 22958975). The phase not confirmed in any of these patients. Additional patients with this variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 19588081, 29122469), or the in trans data had been counted towards another variant and therefore were not included here to avoid circular logic (c.1933G>A (p.Asp645Asn), (PMID 23601496). The data meet PP4 and PM3_Supporting. There is a ClinVar entry for this variant (Variant ID: 286229; 2 star review status) with three submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

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

From Invitae, SCV001379737.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Thr834Argfs*49) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Pompe disease (PMID: 30564623, 29122469, 19588081, 22958975). ClinVar contains an entry for this variant (Variation ID: 286229). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.

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

From Broad Institute Rare Disease Group, Broad Institute, SCV001423058.1

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

Description

The p.Thr834ArgfsTer49 variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22958975, 23601496, 29122469, 19588081), and has also been reported pathogenic by EGL and likely pathogenic by Tehran Medical Genetics Laboratory and Integrated Genetics in ClinVar (Variation ID: 286229). This variant has been identified in 0.0058% (2/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043343). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 834 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a reported pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Thr834ArgfsTer49 variant is pathogenic (PMID: 19588081). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in a dried blood spot or muscle tissue, consistent with disease (PMID: 22958975, 23601496). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting, PP4 (Richards 2015).

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

From Natera, Inc., SCV001463862.1

#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: Aug 27, 2021

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