VCV001339116.4 - ClinVar

NM_000157.4(GBA1):c.492C>G (p.Ser164Arg)

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.

(3)

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, 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.492C>G (p.Ser164Arg)

Variation ID: 1339116 Accession: VCV001339116.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155238613 (GRCh38) [ NCBI UCSC ] 1: 155208404 (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	Feb 4, 2022	Feb 4, 2024	Sep 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000157.4:c.492C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000148.2:p.Ser164Arg	missense
NM_001005741.3:c.492C>G	NP_001005741.1:p.Ser164Arg	missense
NM_001005742.3:c.492C>G	NP_001005742.1:p.Ser164Arg	missense
NM_001171811.2:c.231C>G	NP_001165282.1:p.Ser77Arg	missense
NM_001171812.2:c.345C>G	NP_001165283.1:p.Ser115Arg	missense
NC_000001.11:g.155238613G>C
NC_000001.10:g.155208404G>C
NG_009783.1:g.11085C>G
NG_042867.1:g.5075G>C

... more HGVS ... less HGVS

Protein change

S115R, S164R, S77R

Other names

Canonical SPDI

NC_000001.11:155238612:G:C

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.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Links

dbSNP: rs746019841 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	408
LOC106627981	-	-	-	GRCh38 GRCh38	-	362

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 type I	Likely pathogenic (1)	criteria provided, single submitter	-	RCV001823570.3
Gaucher disease	Likely pathogenic (1)	criteria provided, single submitter	Aug 16, 2022	RCV002282581.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Sep 16, 2022	RCV003146246.3

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073106.1 First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022	Comment: The missense variant p.S164R in GBA (NM_000157.3) has been reported previously in patients with Gaucher disease (Hassan et al, 2018; Sheth et al, 2019). The … (more) The missense variant p.S164R in GBA (NM_000157.3) has been reported previously in patients with Gaucher disease (Hassan et al, 2018; Sheth et al, 2019). The p.S164R variant is observed in 5/30,616 (0.0163%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. 3 variants within 6 amino acid positions of the variant p.S164R have been shown to be pathogenic, while none have been shown to be benign. The p.S164R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 164 of GBA is conserved in all mammalian species. The nucleotide c.492 in GBA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Motor delay (present) , Pancytopenia (present) , Splenomegaly (present) , Seizure (present) , Muscle stiffness (present) , Hoarse cry (present) , Abnormal circulating enzyme concentration … (more) Motor delay (present) , Pancytopenia (present) , Splenomegaly (present) , Seizure (present) , Muscle stiffness (present) , Hoarse cry (present) , Abnormal circulating enzyme concentration or activity (present) (less)
Likely pathogenic (Aug 16, 2022)	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: SCV002572079.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (6) PubMed: 25482214‚ 33301762‚ 30285649‚ 34280392‚ 32707456‚ 29980418 Comment: Variant summary: GBA c.492C>G (p.Ser164Arg) 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.492C>G (p.Ser164Arg) 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 allele was found at a frequency of 2e-05 in 251182 control chromosomes (gnomAD). c.492C>G (also known as S125R) has been reported in the literature as a homozygous and compound heterozygous genotype among individuals affected with Gaucher Disease (examples: Agarwal_2015, Hassan_2018, Sheth_2018 and Thomas_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Sep 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003832898.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024

Comment:

The missense variant p.S164R in GBA (NM_000157.3) has been reported previously in patients with Gaucher disease (Hassan et al, 2018; Sheth et al, 2019). The p.S164R variant is observed in 5/30,616 (0.0163%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. 3 variants within 6 amino acid positions of the variant p.S164R have been shown to be pathogenic, while none have been shown to be benign. The p.S164R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 164 of GBA is conserved in all mammalian species. The nucleotide c.492 in GBA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

Variant summary: GBA c.492C>G (p.Ser164Arg) 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 allele was found at a frequency of 2e-05 in 251182 control chromosomes (gnomAD). c.492C>G (also known as S125R) has been reported in the literature as a homozygous and compound heterozygous genotype among individuals affected with Gaucher Disease (examples: Agarwal_2015, Hassan_2018, Sheth_2018 and Thomas_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. 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
Levels of Lyso GL-1 in Gaucher and Lyso GL-3 in Fabry patients from India: Diagnostic aids for these lysosomal storage disorders.	Verma J	Clinica chimica acta; international journal of clinical chemistry	2021	PMID: 34280392
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
Novel and reported variants in Parkinson's disease genes confer high disease burden among Indians.	Kumar S	Parkinsonism & related disorders	2020	PMID: 32707456
Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India.	Sheth J	BMC medical genetics	2018	PMID: 30285649
Alleles with more than one mutation can complicate genotype/phenotype studies in Mendelian disorders: Lessons from Gaucher disease.	Hassan S	Molecular genetics and metabolism	2018	PMID: 29980418
The face of lysosomal storage disorders in India: a need for early diagnosis.	Agarwal S	Indian journal of pediatrics	2015	PMID: 25482214

Text-mined citations for rs746019841 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 06, 2024

ClinVar Genomic variation as it relates to human health

NM_000157.4(GBA1):c.492C>G (p.Ser164Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs746019841 ...