NM_000157.4(GBA1):c.703T>C (p.Ser235Pro) AND Gaucher disease

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 13, 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:: RCV000020157.16

Allele description [Variation Report for NM_000157.4(GBA1):c.703T>C (p.Ser235Pro)]

NM_000157.4(GBA1):c.703T>C (p.Ser235Pro)

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.703T>C (p.Ser235Pro)

HGVS:

NC_000001.11:g.155238192A>G
NG_009783.1:g.11506T>C
NG_042867.1:g.4654A>G
NM_000157.4:c.703T>CMANE SELECT
NM_001005741.2(GBA):c.703T>C
NM_001005741.3:c.703T>C
NM_001005742.3:c.703T>C
NM_001171811.2:c.442T>C
NM_001171812.2:c.556T>C
NP_000148.2:p.Ser235Pro
NP_001005741.1:p.Ser235Pro
NP_001005742.1:p.Ser235Pro
NP_001165282.1:p.Ser148Pro
NP_001165283.1:p.Ser186Pro
NC_000001.10:g.155207983A>G
NM_000157.2:c.703T>C
NM_000157.3:c.703T>C
NM_001005741.1:c.703T>C
NM_001005741.2(GBA):c.703T>C
NM_001005741.2:c.703T>C
NM_001005741.3:c.703T>C
NM_001005742.2:c.703T>C
NM_001171811.1:c.442T>C
P04062:p.Ser235Pro

Protein change:

S148P

Links:

UniProtKB: P04062#VAR_003278; dbSNP: rs1064644

NCBI 1000 Genomes Browser:

rs1064644

Molecular consequence:

NM_000157.4:c.703T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.703T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.703T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.442T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.556T>C - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040484	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000697593	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 19, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10649495, 10796875 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001422526	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 13, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 12204005, 28727984, 10649495, 22526844, 10796875, 25741868 Citation Link,
SCV002086473	Natera, Inc.	no assertion criteria provided	Pathogenic (May 6, 2017)	germline	clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Type 2 Gaucher disease: the collodion baby phenotype revisited.

Stone DL, Carey WF, Christodoulou J, Sillence D, Nelson P, Callahan M, Tayebi N, Sidransky E.

Arch Dis Child Fetal Neonatal Ed. 2000 Mar;82(2):F163-6.

PubMed [citation]

PMID:: 10685993
PMCID:: PMC1721053

Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients.

Filocamo M, Mazzotti R, Stroppiano M, Seri M, Giona F, Parenti G, Regis S, Corsolini F, Zoboli S, Gatti R.

Hum Mutat. 2002 Sep;20(3):234-5.

PubMed [citation]

PMID:: 12204005

See all PubMed Citations (7)

Details of each submission

From GeneReviews, SCV000040484.3

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

#	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, SCV000697593.1

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

Description

Variant summary: The GBA c.703T>C (p.Ser235Pro) missense variant (alternatively also known as S196P) involves the alteration of a non-conserved nucleotide, is located in glycosyl hydrolase family 30, TIM-barrel domain of the protein (InterPro) and is predicted to be damaging by 3/4 in silico tools. This variant was found in 1/120788 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant has been reported in at least six patients with Gaucher disease in homozygous as well as in compound heterozygous state with other pathogenic variants (Hodanova_1999, Stone_2000, Koprivica_2000, Filocamo_2002), including evidence of cosegregation with disease in one family. Two homozygous patients had type 2 GD, suggesting it could be a severe mutation. An in-vitro study in recombinant virus system showed that this variant severely reduces enzymatic activity (5.07+/-0.49% of normal activity) without affecting protein expression and such enzymatic deficiency is consistent with that seen in patient cells (Stone_2000, Hodanova_2003). One reputable database (via ClinVar) has classified it 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422526.2

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

Description

The p.Ser235Pro variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 12204005, 28727984, 22526844, 10796875, 10649495) and has been identified in 0.006% (2/34582) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1064644). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 21072) as pathogenic by Integrated Genetics and Shahid Beheshti University of Medical Sciences. In vitro functional studies provide some evidence that the p.Ser235Pro variant may impact protein function (PMID: 22526844). 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. The presence of this variant in 2 affected homozygotes and in combination with reported pathogenic variants in 4 individuals with Gaucher disease increases the likelihood that the p.Ser235Pro variant is pathogenic (VariationID: 4288, 4290, 65570; PMID: 12204005, 28727984, 22526844, 10796875, 10649495). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on its presence in affected homozygotes and compound heterozygotes, functional studies, and low frequency in the general population. ACMG/AMP Criteria applied: PM3_strong, PS3, PM2 (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 Natera, Inc., SCV002086473.1

#	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

Last Updated: Jul 15, 2024

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