NM_000157.4(GBA):c.661C>A (p.Pro221Thr) AND Gaucher disease

Clinical significance:Likely pathogenic (Last evaluated: Jun 3, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001199857.1

Allele description [Variation Report for NM_000157.4(GBA):c.661C>A (p.Pro221Thr)]

NM_000157.4(GBA):c.661C>A (p.Pro221Thr)

Genes:
LOC106627981:GBA recombination region [Gene]
GBA:glucosylceramidase beta [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_000157.4(GBA):c.661C>A (p.Pro221Thr)
HGVS:
  • NC_000001.11:g.155238234G>T
  • NG_009783.1:g.11464C>A
  • NG_042867.1:g.4696G>T
  • NM_000157.4:c.661C>AMANE SELECT
  • NM_001005741.3:c.661C>A
  • NM_001005742.3:c.661C>A
  • NM_001171811.2:c.400C>A
  • NM_001171812.2:c.514C>A
  • NP_000148.2:p.Pro221Thr
  • NP_001005741.1:p.Pro221Thr
  • NP_001005742.1:p.Pro221Thr
  • NP_001165282.1:p.Pro134Thr
  • NP_001165283.1:p.Pro172Thr
  • NC_000001.10:g.155208025G>T
  • NM_001005741.2:c.661C>A
Protein change:
P134T
Molecular consequence:
  • NM_000157.4:c.661C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005741.3:c.661C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005742.3:c.661C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171811.2:c.400C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171812.2:c.514C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Gaucher disease
Synonyms:
Acute cerebral Gaucher disease; Cerebroside lipidosis syndrome; Gaucher splenomegaly; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0018150; MedGen: C0017205

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001370592Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jun 3, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Novel pathogenic mutations in the glucocerebrosidase locus.

Duran R, McNeill A, Mehta A, Hughes D, Cox T, Deegan P, Schapira AH, Hardy J.

Mol Genet Metab. 2012 Aug;106(4):495-7. doi: 10.1016/j.ymgme.2012.05.006. Epub 2012 May 18.

PubMed [citation]
PMID:
22658918
PMCID:
PMC3426931

Glucocerebrosidase mutations in Gaucher disease.

Beutler E, Demina A, Gelbart T.

Mol Med. 1994 Nov;1(1):82-92.

PubMed [citation]
PMID:
8790604
PMCID:
PMC2229932
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370592.1

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

Description

Variant summary: GBA c.661C>A (p.Pro221Thr, legacy name Pro182Thr) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251024 control chromosomes. c.661C>A has been reported in the literature in at-least one individual affected with Gaucher Disease Type 1 (Beutler_1994) and has been subsequently cited by others (example, Duran_2012, McNeill_2012, Hruska_2008, Atrian_2008, Grabowski_1997). Additional Gaucher Disease patients with this variant have been reported as part of the GAUCHERITE study database (Donald_2019, unpublished data). As the GAUCHERITE study is a multicenter observational stratified medicine project of UK patients with a confirmed biochemical diagnosis of Gaucher disease (NCT03240653), these data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.

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

Last Updated: Jun 14, 2021

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