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NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys) AND Gaucher disease type I

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 22, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000417294.5

Allele description [Variation Report for NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)]

NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)

Genes:
LOC106627981:GBA recombination region [Gene]
GBA1:glucosylceramidase beta 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)
Other names:
R496C
HGVS:
  • NC_000001.11:g.155235003G>A
  • NG_009783.1:g.14695C>T
  • NG_042867.1:g.1465G>A
  • NM_000157.3(GBA):c.1603C>T
  • NM_000157.4:c.1603C>TMANE SELECT
  • NM_001005741.3:c.1603C>T
  • NM_001005742.3:c.1603C>T
  • NM_001171811.2:c.1342C>T
  • NM_001171812.2:c.1456C>T
  • NP_000148.2:p.Arg535Cys
  • NP_001005741.1:p.Arg535Cys
  • NP_001005742.1:p.Arg535Cys
  • NP_001165282.1:p.Arg448Cys
  • NP_001165283.1:p.Arg486Cys
  • NC_000001.10:g.155204794G>A
  • NC_000001.10:g.155204794G>A
  • NM_000157.3(GBA):c.1603C>T
  • NM_000157.3:c.1603C>T
  • NM_000157.4:c.1603C>T
  • NM_001005741.2:c.1603C>T
  • NM_001005741.3:c.1603C>T
  • P04062:p.Arg535Cys
Protein change:
R448C
Links:
UniProtKB: P04062#VAR_003327; dbSNP: rs747506979
NCBI 1000 Genomes Browser:
rs747506979
Molecular consequence:
  • NM_000157.4:c.1603C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005741.3:c.1603C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001005742.3:c.1603C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171811.2:c.1342C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171812.2:c.1456C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Gaucher disease type I (GD1)
Synonyms:
GBA DEFICIENCY; GD I; Gaucher's disease, type 1; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009265; MedGen: C1961835; Orphanet: 355; Orphanet: 77259; OMIM: 230800

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000281966Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
no assertion criteria provided
Likely pathogenic
(Jun 10, 2016) 		unknownresearch

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

SCV001422766Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 22, 2020) 		germlinecuration

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
Bauddha, Maharastrian, Indianunknownyes1not providednot providednot providednot providedresearch

Citations

PubMed

Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease.

Ankleshwaria C, Mistri M, Bavdekar A, Muranjan M, Dave U, Tamhankar P, Khanna V, Jasinge E, Nampoothiri S, Edayankara Kadangot S, Sheth F, Gupta S, Sheth J.

J Hum Genet. 2014 Apr;59(4):223-8. doi: 10.1038/jhg.2014.5. Epub 2014 Feb 13. Erratum in: J Hum Genet. 2015 May;60(5):285. doi: 10.1038/jhg.2015.27.

PubMed [citation]
PMID:
24522292

Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION.

Leija-Salazar M, Sedlazeck FJ, Toffoli M, Mullin S, Mokretar K, Athanasopoulou M, Donald A, Sharma R, Hughes D, Schapira AHV, Proukakis C.

Mol Genet Genomic Med. 2019 Mar;7(3):e564. doi: 10.1002/mgg3.564. Epub 2019 Jan 13.

PubMed [citation]
PMID:
30637984
PMCID:
PMC6418358
See all PubMed Citations (5)

Details of each submission

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000281966.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Bauddha, Maharastrian, Indian1not providednot providedresearch PubMed (1)

Description

USG abdomen s/o. storage disease; Bone-marrow s/o. Storage disease; Anaemia (Hb: 8.6 g%); Plasma Chitotriosidase: 11755.7 nmol/hr/ml plasma (N.R.: 28.66 - 62.94); Beta-Glucosidase: 1.45 nmol/hr/mg protein (N.R.: 4.0 - 32.0)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422766.2

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

Description

The p.Arg535Cys variant in GBA has been reported at least 10 individuals with Gaucher disease (PMID: 27865684, 30637984, 30764785) and has been identified in 0.004% (1/24272) of South Asian chromosomes and 0.004% (1/25702) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747506979). 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: 242383) as likely pathogenic by the Institute of Human Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg535His, has been reported in association with the disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 17059888, 24756352, 17427031, 20629126, 7655857, 28947706, 23430543, 8432537; VariationID: 4311). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on the levels of beta-glucosidase detected in the BGL test being significantly below 8.7 nmol/mg/h consistent with disease (PMID: 27865684). Additionally, the homozygous occurrence of this variant in two affected individuals and the presence of this variant in combination with reported pathogenic variants (VariationID: 4288, 4295, 4290; PMID: 30764785, 27865684, 30637984) and in five individuals with Gaucher disease increases the likelihood that the p.Arg535Cys variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the detection of the variant in combination with other pathogenic variants in affected individuals, the presence of another pathogenic variant at the same location, and the presence of the variant in an individual with a phenotype specific for the disease. ACMG/AMP Criteria applied: PM3_very-Strong, PM2, PM5, PP4 (Richards, 2015).

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

Last Updated: Oct 8, 2024