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NM_000152.5(GAA):c.841C>T (p.Arg281Trp) AND GAA-related disorder

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 9, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004751427.1

Allele description [Variation Report for NM_000152.5(GAA):c.841C>T (p.Arg281Trp)]

NM_000152.5(GAA):c.841C>T (p.Arg281Trp)

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.841C>T (p.Arg281Trp)
Other names:
NM_000152.5(GAA):c.841C>T
HGVS:
  • NC_000017.11:g.80107705C>T
  • NG_009822.1:g.11150C>T
  • NM_000152.5:c.841C>TMANE SELECT
  • NM_001079803.3:c.841C>T
  • NM_001079804.3:c.841C>T
  • NP_000143.2:p.Arg281Trp
  • NP_001073271.1:p.Arg281Trp
  • NP_001073272.1:p.Arg281Trp
  • LRG_673t1:c.841C>T
  • LRG_673:g.11150C>T
  • NC_000017.10:g.78081504C>T
  • NC_000017.10:g.78081504C>T
  • NM_000152.3:c.841C>T
  • NM_000152.4(GAA):c.841C>T
  • NM_000152.4:c.841C>T
  • NM_001079803.2:c.841C>T
  • p.Arg281Trp
Protein change:
R281W
Links:
dbSNP: rs142967546
NCBI 1000 Genomes Browser:
rs142967546
Molecular consequence:
  • NM_000152.5:c.841C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.841C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.841C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
GAA-related disorder
Synonyms:
GAA-related condition
Identifiers:

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV005351834PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Likely pathogenic
(Sep 9, 2024)
germlineclinical testing

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005351834.1

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

Description

The GAA c.841C>T variant is predicted to result in the amino acid substitution p.Arg281Trp. This variant has been reported along with a second causative variant in individuals with late-onset Pompe disease (LOPD) or by newborn screening (Ficicioglu et al. 2020. PubMed ID: 33202836; Wencel et al. 2021. PubMed ID: 36299500). This variant was also reported in an individual with LOPD and an individual identified by newborn screening; a second variant was not identified in either individual (Angelini et al. 2012. PubMed ID: 22081099; Wittmann et al. 2012. PubMed ID: 23430949). It was also identified along with a likely benign intronic variant in an individual diagnosed with Pompe disease (Table S3, Kishnani et al. 2019. PubMed ID: 31086307). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from pathogenic to uncertain significance (http://www.ncbi.nlm.nih.gov/clinvar/variation/283894). The ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel interprets this variant as likely pathogenic and cites internal data from clinical diagnostic laboratories in their interpretation, mentioning the c.841C>T (p.Arg281Trp) variant was found with a second pathogenic variant (c.2481+102_2646+31del or c.2161del) in two individuals, with the variants confirmed to be on opposite alleles (i.e., in trans) in one of the individuals. Based on the collective evidence, we interpret this variant as likely pathogenic.

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

Last Updated: Oct 20, 2024