NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000079343.34

Allele description

NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)

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.1504C>T (p.Arg502Cys)

Other names:

R463C; (p.Arg502Cys)

HGVS:

NC_000001.11:g.155235196G>A
NG_009783.1:g.14502C>T
NG_042867.1:g.1658G>A
NM_000157.4:c.1504C>TMANE SELECT
NM_001005741.3:c.1504C>T
NM_001005742.3:c.1504C>T
NM_001171811.2:c.1243C>T
NM_001171812.2:c.1357C>T
NP_000148.2:p.Arg502Cys
NP_001005741.1:p.Arg502Cys
NP_001005741.1:p.Arg502Cys
NP_001005742.1:p.Arg502Cys
NP_001165282.1:p.Arg415Cys
NP_001165283.1:p.Arg453Cys
NC_000001.10:g.155204987G>A
NM_000157.2:c.1504C>T
NM_000157.3:c.1504C>T
NM_000157.4:c.1504C>T
NM_001005741.2(GBA):c.1504C>T
NM_001005741.2:c.1504C>T
NM_001005742.2:c.1504C>T
NM_001005742.3:c.1504C>T
P04062:p.Arg502Cys
c.1504C>T (p.Arg502Cys)

Protein change:

R415C; ARG463CYS

Links:

UniProtKB: P04062#VAR_003324; OMIM: 606463.0008; dbSNP: rs80356771

NCBI 1000 Genomes Browser:

rs80356771

Molecular consequence:

NM_000157.4:c.1504C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.1504C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.1504C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000225256	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Jul 24, 2012)	germline	clinical testing	Citation Link,
SCV000329942	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 2, 2022)	germline	clinical testing	Citation Link,
SCV000964939	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1972019, 8733893, 17427031, 21704274, 24482953, 8294487, 11259172, 28492532
SCV002024205	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002048388	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Sep 23, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sequence of two alleles responsible for Gaucher disease.

Hong CM, Ohashi T, Yu XJ, Weiler S, Barranger JA.

DNA Cell Biol. 1990 May;9(4):233-41.

PubMed [citation]

PMID:: 1972019

Genotype D399N/R463C in a patient with type 3 Gaucher disease previously assigned genotype N370S/R463C.

Tayebi N, Herman J, Ginns EI, Sidransky E.

Biochem Mol Med. 1996 Apr;57(2):149-51.

PubMed [citation]

PMID:: 8733893

See all PubMed Citations (9)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000225256.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		6	not provided	not provided	not provided

From GeneDx, SCV000329942.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate that R502C has reduced enzyme activity (Hong et al., 1990; Grace et al., 1994); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as R463C due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 12595585, 30537300, 10796875, 23413260, 22975760, 23588557, 24482953, 16293621, 8294487, 1972019, 1348297, 19286695, 27717005, 29140481, 8733893, 26008600, 9279145, 29625052, 34426522, 32658388)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000964939.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 502 of the GBA protein (p.Arg502Cys). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with Gaucher disease and Parkinson's disease (PMID: 1972019, 8733893, 17427031, 21704274, 24482953). This variant is also known as p.Arg463Cys or R463C. ClinVar contains an entry for this variant (Variation ID: 4295). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 11259172). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024205.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048388.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The GBA c.1504C>T; p.Arg502Cys variant (rs80356771), also known as Arg463Cys, is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Gaucher syndrome (Alfonso 2007, Chauhan 2013, Hatton 1997, Tayebi 1996). Functional analyses of the variant protein show a dramatic reduction in GBA enzyme activity (Grace 1994, Liou 2006). This variant is also reported in ClinVar (Variation ID: 4295). This variant is found in the non-Finnish European population with an allele frequency of 0.011% (14/128876 alleles) in the Genome Aggregation Database. The arginine at codon 502 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.817). Additionally, other amino acid substitutions at this codon (His, Pro, Cys, Gln, Ser) have been reported in individuals with Gaucher syndrome (Alfonso 2007, Liou 2006, Beutler 1994, Jurecka 2011). Based on available information, this variant is considered to be pathogenic. References: Alfonso P et al. Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. J Hum Genet. 2007;52(5):391-396.PMID: 17427031. Beutler E et al. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994 Nov;1(1):82-92. PMID: 8790604. Chauhan V et al. Adult type 3 Gaucher disease as manifestation of R463C/Rec Nci I mutation: first reported case in the world literature. J Assoc Physicians India. 2013 May;61(5):346-8. PMID: 24482953. Grace ME et al. Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994 Jan 21;269(3):2283-91. PMID: 8294487. Hatton CE et al. Mutation analysis in 46 British and Irish patients with Gaucher's disease. Arch Dis Child. 1997 Jul;77(1):17-22. PMID: 9279145. Jurecka A et al. Gaucher disease and dysgammaglobulinemia: a report of 61 patients, including 18 with GD type III. Blood Cells Mol Dis. 2011 Jan 15;46(1):85-7. PMID: 20729110. Liou B et al. Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. J Biol Chem. 2006 Feb 17;281(7):4242-53. PMID: 16293621. Tayebi N et al. Genotype D399N/R463C in a patient with type 3 Gaucher disease previously assigned genotype N370S/R463C. Biochem Mol Med. 1996 Apr;57(2):149-51. PMID: 8733893.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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