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

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jun 24, 2022
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:: RCV000020151.19

Allele description [Variation Report for NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)]

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

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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Chain C, Apolipoprotein A-I
Chain C, Apolipoprotein A-I
gi|1534918264|pdb|6CM1|C

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040478	GeneReviews	no classification provided	not provided	germline	literature only
SCV000697584	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 25, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9279145, 8294487, 10796875 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002086448	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV002557873	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10796875, 11259172, 30764785, 31010158, 33334373, 25741868
SCV002761818	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046060	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Mutation analysis in 46 British and Irish patients with Gaucher's disease.

Hatton CE, Cooper A, Whitehouse C, Wraith JE.

Arch Dis Child. 1997 Jul;77(1):17-22.

PubMed [citation]

PMID:: 9279145
PMCID:: PMC1717235

Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression.

Grace ME, Newman KM, Scheinker V, Berg-Fussman A, Grabowski GA.

J Biol Chem. 1994 Jan 21;269(3):2283-91.

PubMed [citation]

PMID:: 8294487

See all PubMed Citations (8)

Details of each submission

From GeneReviews, SCV000040478.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697584.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The GBA c.1504C>T (p.Arg502Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change within the glycosyl hydrolase family 30, beta sandwich domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/121382 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients with Gaucher disease type I and type III, both as a compound heterozygous and homozygous allele. The variant is considered a recurrent mutation and has been associated with mild and severe Gaucher-related phenotypes in patients. Functional studies showed a significant reduction in enzyme activity (Grace_1994). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is 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 Natera, Inc., SCV002086448.1

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557873.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Gaucher disease is associated with marked clinical variability, even within the same family (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 beta sandwich domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Arg463Cys) in the literature. It has previously been reported in >20 Gaucher disease type 1 and 3 patients, however the phenotypic consequence of this variant has been suggested as being particularly inconsistent (ClinVar, PMIDs: 10796875; 33334373; 30764785). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated that this variant results in reduced GBA enzymatic activity (PMID: 11259172). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761818.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046060.1

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

Description

This variant is also known as p.Arg463Cys in the literature (PMID: 23588557). This variant has been previously reported as a compound heterozygous change most commonly in patients with Gaucher disease, but also among patients with Parkinson disease and renal cell carcinoma (PMID: 1972019, 24482953, 8733893, 17427031, 21704274, 29625052, 30537300). Functional studies indicate that this variant impairs the GBA enzyme activity (PMID: 11259172, 8294487). The frequency data for variants in the GBA gene in population databases may be unreliable due to the presence of pseudogenes and paralogs (PMID: 20301446). In silico analyses support a deleterious effect of the c.1504C>T (p.Arg502Cys) variant on protein function. Based on the available evidence, the c.1504C>T (p.Arg502Cys) variant is classified as Pathogenic.

#	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

Last Updated: Oct 8, 2024

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