VCV002503945.1 - ClinVar

NM_000157.4(GBA1):c.1215C>A (p.Ser405Arg)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000157.4(GBA1):c.1215C>A (p.Ser405Arg)

Variation ID: 2503945 Accession: VCV002503945.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155236254 (GRCh38) [ NCBI UCSC ] 1: 155206045 (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	Jun 4, 2023	Jun 3, 2023	Apr 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000157.4:c.1215C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000148.2:p.Ser405Arg	missense
NM_001005741.2:c.1215C>A
NM_001005741.3:c.1215C>A	NP_001005741.1:p.Ser405Arg	missense
NM_001005742.3:c.1215C>A	NP_001005742.1:p.Ser405Arg	missense
NM_001171811.2:c.954C>A	NP_001165282.1:p.Ser318Arg	missense
NM_001171812.2:c.1068C>A	NP_001165283.1:p.Ser356Arg	missense
NC_000001.11:g.155236254G>T
NC_000001.10:g.155206045G>T
NG_009783.1:g.13444C>A
NG_042867.1:g.2716G>T

... more HGVS ... less HGVS

Protein change

S318R, S356R, S405R

Other names

Canonical SPDI

NC_000001.11:155236253:G: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	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2023	RCV003230936.1

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.
Likely pathogenic (Apr 26, 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: SCV003929092.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (5) PubMed: 24022302‚ 30461613‚ 24904648‚ 31816052‚ 32702516 Comment: Variant summary: GBA c.1215C>A (p.Ser405Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded … (more) Variant summary: GBA c.1215C>A (p.Ser405Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251312 control chromosomes. c.1215C>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Gaucher Disease (example, Malini_2014, Miano_2020, Costa_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Malini_2014). The most pronounced variant effect results in a near complete loss of GBA activity in transiently transfected cells. The following publications have been ascertained in the context of this evaluation (PMID: 31816052, 30461613, 24022302, 24904648, 32702516). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)

Comment:

Variant summary: GBA c.1215C>A (p.Ser405Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251312 control chromosomes. c.1215C>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Gaucher Disease (example, Malini_2014, Miano_2020, Costa_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Malini_2014). The most pronounced variant effect results in a near complete loss of GBA activity in transiently transfected cells. The following publications have been ascertained in the context of this evaluation (PMID: 31816052, 30461613, 24022302, 24904648, 32702516). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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
Defective FAS-Mediated Apoptosis and Immune Dysregulation in Gaucher Disease.	Miano M	The journal of allergy and clinical immunology. In practice	2020	PMID: 32702516
A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models.	Costa R	Human molecular genetics	2020	PMID: 31816052
Three mutations of adult type 1 Gaucher disease found in a Chinese patient: A case report.	Du X	Medicine	2018	PMID: 30461613
In silico identification of genetic variants in glucocerebrosidase (GBA) gene involved in Gaucher's disease using multiple software tools.	Manickam M	Frontiers in genetics	2014	PMID: 24904648
Functional analysis of 11 novel GBA alleles.	Malini E	European journal of human genetics : EJHG	2014	PMID: 24022302

Text-mined citations for this variant ...

Record last updated Jun 10, 2023

ClinVar Genomic variation as it relates to human health

NM_000157.4(GBA1):c.1215C>A (p.Ser405Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...