VCV002682534.2 - ClinVar

NM_000157.4(GBA1):c.1193G>A (p.Arg398Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000157.4(GBA1):c.1193G>A (p.Arg398Gln)

Variation ID: 2682534 Accession: VCV002682534.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155236276 (GRCh38) [ NCBI UCSC ] 1: 155206067 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 6, 2024	Jan 26, 2024	Nov 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000157.4:c.1193G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000148.2:p.Arg398Gln	missense
NM_001005741.3:c.1193G>A	NP_001005741.1:p.Arg398Gln	missense
NM_001005742.3:c.1193G>A	NP_001005742.1:p.Arg398Gln	missense
NM_001171811.2:c.932G>A	NP_001165282.1:p.Arg311Gln	missense
NM_001171812.2:c.1046G>A	NP_001165283.1:p.Arg349Gln	missense
NC_000001.11:g.155236276C>T
NC_000001.10:g.155206067C>T
NG_009783.1:g.13422G>A
NG_042867.1:g.2738C>T

... more HGVS ... less HGVS

Protein change

R311Q, R349Q, R398Q

Other names

p.Arg398Gln

Canonical SPDI

NC_000001.11:155236275:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GBA1		-	-	GRCh38 GRCh38 GRCh37	32	406
LOC106627981	-	-	-	GRCh38 GRCh38	-	360

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Gaucher disease	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2023	RCV003479907.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 28, 2022	RCV003482466.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 15, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Gaucher disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004222668.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (4) PubMed: 10757640‚ 1487244‚ 34134921‚ 34282371 Comment: Variant summary: GBA c.1193G>A (p.Arg398Gln) results in a conservative amino acid change located in the glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded … (more) Variant summary: GBA c.1193G>A (p.Arg398Gln) results in a conservative amino acid change located in the glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251386 control chromosomes (gnomAD). c.1193G>A has been reported in the literature in multiple individuals affected with Gaucher Disease (e.g. Kawame_1992, Amaral_2000, Mozafari_2021, Silva Garcia_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Amaral_2000). The most pronounced variant effect results in <10% of wild type enzymatic activity. The following publications have been ascertained in the context of this evaluation (PMID: 10757640, 1487244, 34282371, 34134921). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Dec 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004228230.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (9) PubMed: 17427031‚ 24522292‚ 27334896‚ 29656334‚ 33301762‚ 34282371‚ 34440436‚ 7627184‚ 8829663 Comment: PP3, PP4, PM2, PM5, PS4_moderate Number of individuals with the variant: 1

Comment:

Variant summary: GBA c.1193G>A (p.Arg398Gln) results in a conservative amino acid change located in the glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251386 control chromosomes (gnomAD). c.1193G>A has been reported in the literature in multiple individuals affected with Gaucher Disease (e.g. Kawame_1992, Amaral_2000, Mozafari_2021, Silva Garcia_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Amaral_2000). The most pronounced variant effect results in <10% of wild type enzymatic activity. The following publications have been ascertained in the context of this evaluation (PMID: 10757640, 1487244, 34282371, 34134921). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center.	Barbosa-Gouveia S	Genes	2021	PMID: 34440436
Analysis of glucocerebrosidase (GBA) gene mutations in Iranian patients with Gaucher disease.	Mozafari H	Iranian journal of child neurology	2021	PMID: 34282371
Gaucher Disease: Identification and Novel Variants in Mexican and Spanish Patients.	Silva García R	Archives of medical research	2021	PMID: 34134921
Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease.	Thomas DC	Clinical biochemistry	2021	PMID: 33301762
Four Gaucher disease type II patients with three novel mutations: a single centre experience from Turkey.	Bulut FD	Metabolic brain disease	2018	PMID: 29656334
Rare Case of Hepatic Gaucheroma in a Child on Enzyme Replacement Therapy.	Korula S	JIMD reports	2017	PMID: 27334896
Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease.	Ankleshwaria C	Journal of human genetics	2014	PMID: 24522292
Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain.	Alfonso P	Journal of human genetics	2007	PMID: 17427031
Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients.	Amaral O	European journal of human genetics : EJHG	2000	PMID: 10757640
Two novel (1098insA and Y313H) and one rare (R359Q) mutations detected in exon 8 of the beta-glucocerebrosidase gene in Gaucher's disease patients.	Cormand B	Human mutation	1996	PMID: 8829663
Gaucher disease in Spanish patients: analysis of eight mutations.	Cormand B	Human mutation	1995	PMID: 7627184
Rapid identification of mutations in the glucocerebrosidase gene of Gaucher disease patients by analysis of single-strand conformation polymorphisms.	Kawame H	Human genetics	1992	PMID: 1487244
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Text-mined citations for this variant ...

Record last updated Jan 26, 2024

ClinVar Genomic variation as it relates to human health

NM_000157.4(GBA1):c.1193G>A (p.Arg398Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...