NM_000152.5(GAA):c.1905C>A (p.Asn635Lys) AND Glycogen storage disease, type II

Clinical significance:Pathogenic (Last evaluated: Oct 26, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000780271.2

Allele description [Variation Report for NM_000152.5(GAA):c.1905C>A (p.Asn635Lys)]

NM_000152.5(GAA):c.1905C>A (p.Asn635Lys)

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.1905C>A (p.Asn635Lys)
Other names:
NM_000152.5:c.1905C>A
HGVS:
  • NC_000017.11:g.80112892C>A
  • NG_009822.1:g.16337C>A
  • NM_000152.5:c.1905C>AMANE SELECT
  • NM_001079803.3:c.1905C>A
  • NM_001079804.3:c.1905C>A
  • NP_000143.2:p.Asn635Lys
  • NP_001073271.1:p.Asn635Lys
  • NP_001073272.1:p.Asn635Lys
  • LRG_673t1:c.1905C>A
  • LRG_673:g.16337C>A
  • NC_000017.10:g.78086691C>A
  • NM_000152.3:c.1905C>A
Protein change:
N635K
Links:
dbSNP: rs1414146587
NCBI 1000 Genomes Browser:
rs1414146587
Molecular consequence:
  • NM_000152.5:c.1905C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.1905C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.1905C>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
SCV000917398Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 26, 2018)
germlineclinical testing

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

Citation Link,

SCV001422990Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 15, 2020)
germlinecuration

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations.

Oba-Shinjo SM, da Silva R, Andrade FG, Palmer RE, Pomponio RJ, Ciociola KM, S Carvalho M, Gutierrez PS, Porta G, Marrone CD, Munoz V, Grzesiuk AK, Llerena JC Jr, Berditchevsky CR, Sobreira C, Horovitz D, Hatem TP, Frota ER, Pecchini R, Kouyoumdjian JA, Werneck L, Amado VM, et al.

J Neurol. 2009 Nov;256(11):1881-90. doi: 10.1007/s00415-009-5219-y. Epub 2009 Jul 9.

PubMed [citation]
PMID:
19588081

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917398.1

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

Description

Variant summary: GAA c.1905C>A (p.Asn635Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 237820 control chromosomes. c.1905C>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect was estimated to result in 10%-<30% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 Broad Institute Rare Disease Group, Broad Institute, SCV001422990.1

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

Description

The p.Asn635Lys variant in GAA has been reported in at least 5 individuals with glycogen storage disease II (PMID: 19588081, 22644586, 22658377) and has been identified in 0.003% (1/33926) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1414146587). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using cells transfected with the variant provide some evidence that the p.Asn635Lys variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in the homozygous state and in combination with reported pathogenic variants in multiple individuals with glycogen storage disease II (PMID: 19588081, 22658377). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2 (Richards 2015).

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

Last Updated: Aug 27, 2021

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