1-155236276-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000157.4(GBA1):c.1193G>A(p.Arg398Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.19

Publications

13 publications found

Variant links:

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

GBA1 Gene-Disease associations (from GenCC):

Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Gaucher disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
Gaucher disease perinatal lethal
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
late-onset Parkinson disease
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Gaucher disease type I
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
Gaucher disease type II
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Gaucher disease type III
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000157.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155236276-C-G is described in CliVar as Pathogenic. Clinvar id is 3385311.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 1-155236276-C-T is Pathogenic according to our data. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4 link	c.1193G>A	p.Arg398Gln	missense_variant	Exon 8 of 11	ENST00000368373.8	NP_000148.2	P04062-1A0A068F658

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 link	c.1193G>A	p.Arg398Gln	missense_variant	Exon 8 of 11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 28, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4, PM2, PM5, PS4_moderate -

Gaucher disease

Pathogenic:1

Nov 15, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

H;H;.;.

PhyloP100

5.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.93

MutPred

0.87

Loss of MoRF binding (P = 0.0482);Loss of MoRF binding (P = 0.0482);.;.;

MVP

0.97

MPC

1.8

ClinPred

0.99

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.96

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over