1-155236384-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP2PP3PP5_Very_Strong

The NM_000157.4(GBA1):c.1085C>T(p.Thr362Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,878 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 (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.33

Publications

10 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 12 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000157.4

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, 0.783

PP5

Variant 1-155236384-G-A is Pathogenic according to our data. Variant chr1-155236384-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4306.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.1085C>T	p.Thr362Ile	missense_variant	Exon 8 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 link	c.1085C>T	p.Thr362Ile	missense_variant	Exon 8 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251480

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

Cov.:

Alfa

AF:

0.0000125

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease

Pathogenic:3

Jan 28, 2022

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.1085C>T (p.Thr362Ile) results in a non-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 allele was found at a frequency of 1.2e-05 in 251480 control chromosomes (gnomAD). c.1085C>T has been reported in the literature in individuals affected with Gaucher Disease (He_1992, Erdos_2007, Lo_2011, Chan_2011, DAmore_2021). These data indicate that the variant is likely to be associated with disease. Functional studies report specific activity of this variant beta-glucosidases expressed in Sf9 cells was < 10% of normal activity (He_1992, Grace_1994). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 13, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Thr362Ile variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 17395504, 1301953, 25435509, 22713811) and has been identified in 0.003% (3/113762) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs76539814). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Thr362Ile variant may slightly impact protein function (PMID: 1301953, 22713811). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants and in 4 individuals with Gaucher disease increases the likelihood that the p.Thr362Ile variant is pathogenic (VariationID: 4295, 4288; PMID: 17395504, 1301953, 25435509, 22713811). The phenotype of an individual heterozygous for this variant is highly specific for Gaucher disease based on beta-glucosidase assays showing <10% of normal enzyme activity, consistent with disease (PMID: 1301953). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on multiple occurrences with pathogenic variants in affected individuals, low frequency in the general population, and in vitro functional studies. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PP3, PP4 (Richards 2015). -

Jan 21, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Gaucher disease type I

Pathogenic:1

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset

Pathogenic:1

Dec 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jun 22, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gaucher disease type II

Pathogenic:1

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

D;D;.;.

Eigen

Benign

-0.065

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

1.6

L;L;.;.

PhyloP100

4.3

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.54

T;T;T;T

Polyphen

0.39

B;B;.;.

Vest4

0.65

MVP

0.91

MPC

1.6

ClinPred

0.51

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.90

Mutation Taster

=0/100

disease causing (ClinVar)

(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