NM_000157.4(GBA1):c.1604G>A (p.Arg535His) AND Gaucher disease type I

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Oct 15, 2020
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:: RCV000004553.26

Allele description [Variation Report for NM_000157.4(GBA1):c.1604G>A (p.Arg535His)]

NM_000157.4(GBA1):c.1604G>A (p.Arg535His)

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.1604G>A (p.Arg535His)

Other names:

R496H

HGVS:

NC_000001.11:g.155235002C>T
NG_009783.1:g.14696G>A
NG_042867.1:g.1464C>T
NM_000157.3(GBA):c.1604G>A
NM_000157.4:c.1604G>AMANE SELECT
NM_001005741.3:c.1604G>A
NM_001005742.3:c.1604G>A
NM_001171811.2:c.1343G>A
NM_001171812.2:c.1457G>A
NP_000148.2:p.Arg535His
NP_001005741.1:p.Arg535His
NP_001005742.1:p.Arg535His
NP_001165282.1:p.Arg448His
NP_001165283.1:p.Arg486His
NC_000001.10:g.155204793C>T
NM_000157.2:c.1604G>A
NM_000157.3(GBA):c.1604G>A
NM_000157.3:c.1604G>A
NM_000157.4:c.1604G>A
NM_001005741.2:c.1604G>A
NM_001005741.3:c.1604G>A
NM_001005742.2:c.1604G>A
P04062:p.Arg535His
c.1604G>A (p.Arg535His)

Protein change:

R448H; ARG496HIS

Links:

UniProtKB: P04062#VAR_003328; OMIM: 606463.0022; dbSNP: rs75822236

NCBI 1000 Genomes Browser:

rs75822236

Molecular consequence:

NM_000157.4:c.1604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.1604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.1604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.1343G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.1457G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024727	OMIM	no assertion criteria provided	Pathogenic (Jun 15, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000223929	Knight Diagnostic Laboratories, Oregon Health and Sciences University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000966890	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Dec 6, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8432537, 16293621, 23588557, 23699752, 27735925, 9240741, 12972024, 24033266
SCV001193813	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 19, 2019)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25558695, 8213821, 16293621, 84325327, 12972024, 9240741, 7916532 Citation Link,
SCV001422767	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (9) [See all records that cite these PMIDs] 17427031, 8432537, 23430543, 7655857, 20629126, 28947706, 17059888, 16293621, 25741868 Citation Link,
SCV001437673	Hadassah Hebrew University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 20, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 33223529
SCV002767896	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 15, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23430543, 27735925, 31010158, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	literature only, clinical testing
not provided	germline	no	not provided	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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Beutler E.

Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5384-90. Review.

PubMed [citation]

PMID:: 8516282
PMCID:: PMC46724

A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.

Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, De Deyn PP, Van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, et al.

JAMA Neurol. 2013 Jun;70(6):727-35. doi: 10.1001/jamaneurol.2013.1925.

PubMed [citation]

PMID:: 23588557
PMCID:: PMC3841974

See all PubMed Citations (22)

Details of each submission

From OMIM, SCV000024727.4

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

Description

In 4 unrelated patients, 3 Jewish and 1 non-Jewish European, with type I Gaucher disease (230800), Beutler et al. (1993) identified a heterozygous 1604G-A transition (6683 in the genomic DNA sequence) in the GBA gene, resulting in an arg496-to-his (R496H) substitution. Age at diagnosis varied from 16 to 27 years. None had neurologic findings. Severity score varied from 2 to 9. The other mutation in 3 of the patients was that referred to as 84GG (606463.0014); the fourth patient, Jewish, had the common N370S mutation (606463.0003).

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

From Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV000223929.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966890.1

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

Description

The p.Arg535His (also known as p.Arg496His) variant in GBA has been reported in >20 compound heterozygous individuals (majority of Ashkenazi Jewish origin) with mild forms of Gaucher disease type I (Beutler 1993, Brautbar 2003, Yang 2017). This variant is considered a mild variant, with compound heterozygotes typically presenting as asymptomatic to mild, non-neurological cases (Brautbar 2003, Yang 2017). No homozygotes have been reported, and it is hypothesized that homozygot es may be asymptomatic. This variant was also identified in 0.25% (22/8934) of A shkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID# 4311). In vitro functional studies support an impact on p rotein function (Liou 2006, Choy 1996). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Gaucher disease. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PS4_Moderate.

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

From Myriad Genetics, Inc., SCV001193813.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

NM_001005741.2(GBA):c.1604G>A(R535H, aka R496H) is classified as pathogenic in the context of Gaucher disease and is associated with Type 1 form of disease. Sources cited for classification include the following: PMID 25558695, 8213821, 16293621, 84325327, 12972024, 9240741 and 7916532. Classification of NM_001005741.2(GBA):c.1604G>A(R535H, aka R496H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422767.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (9)

Description

The p.Arg535His variant in GBA has been reported in at least 24 individuals with Gaucher Disease (PMID: 17059888, 24756352, 17427031, 20629126, 7655857, 28947706, 23430543, 8432537) and has been identified in 0.2% (22/8934) of Ashkenazi Jewish chromosomes and 0.011% (2/17404) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75822236). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency taking into consideration that the carrier frequency of GBA variants is increased in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 4311) as pathogenic by EGL Genetic Diagnostics, Knight Diagnostic Laboratories, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. In vitro functional studies showing the variant to result in significantly reduced CRIM specific activity provide some evidence that the p.Arg535His variant may slightly impact protein function (PMID: 16293621). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, the presence of this variant in one affected homozygote and in combination with reported pathogenic variants (VariationID: 4302, 4297, 4290, 4288; PMID: 23430543, 28947706, 20629126, 17059888, 8432537) in 9 individuals with Gaucher disease increases the likelihood that the p.Arg535His variant is pathogenic. The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on beta-glucosidase levels being below the diagnostic cutoff of 8.7nmol/h/mg protein consistent with disease (PMID: 20629126). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg535Cys, has been reported in association with disease in ClinVar and the literature, slightly supporting that a change at this position may not be tolerated (Variation ID: 242383; PMID: 27865684, 30637984, 30764785). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in affected individual and the presence of another pathogenic variant at the same position. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PM2_supporting, PP4, PS3_supporting (Richards 2015).

#	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 Hadassah Hebrew University Medical Center, SCV001437673.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767896.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (OMIM). (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; 27735925). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (34 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) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, also known as R496H in an alternative nomenclature, has been reported in at least 15 patients with Gaucher disease (GD) Type 1. It is often associated with a milder adult-onset GD clinical course, although some patients may experience symptoms during childhood (ClinVar; PMID: 27735925; 23430543). (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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

Relating variation to medicine