NM_000157.4(GBA1):c.680A>G (p.Asn227Ser) AND Gaucher disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 4, 2022
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:: RCV000020156.17

Allele description [Variation Report for NM_000157.4(GBA1):c.680A>G (p.Asn227Ser)]

NM_000157.4(GBA1):c.680A>G (p.Asn227Ser)

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.680A>G (p.Asn227Ser)

Other names:

N188S

HGVS:

NC_000001.11:g.155238215T>C
NG_009783.1:g.11483A>G
NG_042867.1:g.4677T>C
NM_000157.4:c.680A>GMANE SELECT
NM_001005741.2(GBA):c.680A>G
NM_001005741.3:c.680A>G
NM_001005742.3:c.680A>G
NM_001171811.2:c.419A>G
NM_001171812.2:c.533A>G
NP_000148.2:p.Asn227Ser
NP_001005741.1:p.Asn227Ser
NP_001005741.1:p.Asn227Ser
NP_001005742.1:p.Asn227Ser
NP_001165282.1:p.Asn140Ser
NP_001165283.1:p.Asn178Ser
NC_000001.10:g.155208006T>C
NM_000157.2:c.680A>G
NM_000157.3:c.680A>G
NM_001005741.2(GBA):c.680A>G
NM_001005741.2:c.680A>G
NM_001005741.3:c.680A>G
P04062:p.Asn227Ser

Protein change:

N140S; ASN188SER

Links:

UniProtKB: P04062#VAR_003274; OMIM: 606463.0026; dbSNP: rs364897

NCBI 1000 Genomes Browser:

rs364897

Molecular consequence:

NM_000157.4:c.680A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.680A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.680A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.419A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.533A>G - 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
SCV000040483	GeneReviews	no classification provided	not provided	germline	literature only
SCV000697592	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 4, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 24022302, 20729108, 15146461, 21056933, 17395504, 16086325, 20004867, 17427031 Citation Link,
SCV001422959	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 14, 2020)	germline	curation	PubMed (15) [See all records that cite these PMIDs] 30382391, 20729108, 16086325, 8829654, 21056933, 12595585, 30497978, 15146461, 27872820, 26743617, 20004867, 24022302, 17395504, 27865684, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000040483

GeneReviews

no classification provided

not provided

germline

literature only

SCV000697592

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 4, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001422959

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 14, 2020)

germline

curation

PubMed (15)
[See all records that cite these PMIDs]

Citation Link

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

Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain.

Alfonso P, Aznarez S, Giralt M, Pocovi M, Giraldo P; Spanish Gaucher’s Disease Registry..

J Hum Genet. 2007;52(5):391-396. doi: 10.1007/s10038-007-0135-4. Epub 2007 Apr 11. Review.

PubMed [citation]

PMID:: 17427031

Progressive myoclonus epilepsy in Gaucher Disease due to a new Gly-Gly mutation causing loss of an Exonic Splicing Enhancer.

Tonin R, Catarzi S, Caciotti A, Procopio E, Marini C, Guerrini R, Morrone A.

J Neurol. 2019 Jan;266(1):92-101. doi: 10.1007/s00415-018-9084-4. Epub 2018 Oct 31.

PubMed [citation]

PMID:: 30382391
PMCID:: PMC6342868

See all PubMed Citations (16)

Details of each submission

From GeneReviews, SCV000040483.3

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697592.2

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

Description

Variant summary: GBA c.680A>G (p.Asn227Ser) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251308 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (7.2e-05 vs 0.005), allowing no conclusion about variant significance. The variant has been reported in the homozygous and compound heterozygous genotypes in numerous publications of patients with Gaucher Disease and has also been reported in patients in cis with a second variant E326K (example, Alfonso_2007, Biegstraaten_2011, Erdos_2007, Jeong_2011, Tajima_2010). The variant has been shown to result in moderate reductions in enzyme activity via various expression systems (~25%-66% residual activity; Malini_2014, Tajima_2010, Montfort_2004). While the E326K variant does not have a significant effect on enzyme activity in these studies (and has not been observed in GD patients on its own), the addition of the variant of interest resulted in greater effects on activity (completely inactive in one study, 25% residual activity in a second study). Despite the high residual activity reported in these studies, patients with a rare myoclonic epilepsy phenoptype have also been reported in association with the variant (Kowarz_2005). Additionally, in a pair of monozygotic twins, both homozygous for the variant and both having <20% glucocerebrosidase activity in leukocytes, highly discordant manifestations of Gaucher disease were observed: one sister had severe visceral involvment, epilepsy and cerebellar syndrome, while the other had no symptoms of Gaucher disease (Biegstraaten_2011). This report indicates incomplete penetrance and/or variable expressivity, even in individuals having near identical genetic sequence. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these submitters cites overlapping evidences utilized in the context of this evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was re-classified as pathogenic mindful of the caveats of penetrance and expressivity summarized above.

#	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, SCV001422959.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (15)

Description

The p.Asn227Ser variant in GBA has been reported in at least 28 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 20004867, 12595585, 8829654, 20729108, 17395504, 30497978, 27872820, 24022302, 30382391, 15146461, 16086325, 21056933), has been identified in 0.020% (5/24920) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs364897). 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 pathogenic by EGL Genetic Diagnostics and OMIM, and likely pathogenic by Integrated Genetics in ClinVar (Variation ID: 4314). Twins that are monozygous and homozygous for this variant show different clinical presentations, suggesting that there may be incomplete penetrance or variable expressivity associated with this variant. In vitro functional studies provide some evidence that the p.Asn227Ser variant may slightly impact protein function either alone or in cis with another pathogenic variant (PMID: 20004867, 26743617, 27865684, 30497978, 15146461, 24022302). However, these types of assays may not accurately represent biological function. The presence of this variant in 3 affected homozygotes and in combination with at least 7 reported pathogenic variants and in 14 individuals with Gaucher disease increases the likelihood that the p.Asn227Ser variant is pathogenic (PMID: 8829654, 21056933, 12595585, 8829654, 20729108, 30497978, 27872820, 16086325; VariationID: 4302, 4288, 93459, 4290, 99352, 76478, 4297). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Gaucher disease based on low glucocerebrosidase activity consistent with Gaucher disease (PMID: 30382391, 16086325, 21056933). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner with incomplete penetrance or variable expressivity based on multiple occurrences with pathogenic GBA variants in individuals with Gaucher Disease. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PM2_supporting, PS3_supporting, PP4, PP1 (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

Last Updated: Oct 13, 2024

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