1-155238141-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000157.4(GBA1):c.754T>A(p.Phe252Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 6.35

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a helix (size 18) in uniprot entity GBA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000157.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

PP5

Variant 1-155238141-A-T is Pathogenic according to our data. Variant chr1-155238141-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.754T>A	p.Phe252Ile	missense_variant	6/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.754T>A	p.Phe252Ile	missense_variant	6/11	1	NM_000157.4	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

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

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251488

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000274

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2020	Variant summary: GBA c.754T>A (p.Phe252Ile) results in a non-conservative amino acid change located in the Glycosyl hudrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251488 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (4.4e-05 vs 0.005), allowing no conclusion about variant significance. c.754T>A has been reported in the literature in multiple individuals from diverse ethnic backgrounds affected with Gaucher Disease, example, Japanese (Kawame_1991), English (He_1992), Italian (Filocamo_1992), Thai (Suwannarat_2007), and Indian (Sheth_2019), in addition to patients affected with Parkinson's disease (example, Trinh_2019). 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. The most pronounced variant effect results in <10% of normal activity in transient expression of Glucocerebrosidase activity in transfected COS-1 cells (example, Kawame_1991). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic using overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Phe2252Ile variant in GBA has been reported in at least 17 individuals with Gaucher disease and has been identified in 0.010% (2/19954) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs381737). 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: 4301) as pathogenic by EGL Genetic Diagnostics and OMIM. In vitro functional studies provide some evidence that the p.Phe252Ile variant may impact protein function (PMID: 15276648). However, these types of assays may not accurately represent biological function. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Phe at position 252 is highly conserved in mammals and evolutionary distant species, but 1 mammal (Chimp) carries an Ile, raising the possibility that this change at this position may be tolerated. The presence of this variant in 4 affected homozygotes and in combination with reported pathogenic variants in 8 individuals with Gaucher disease increases the likelihood that the p.Phe252Ile variant is pathogenic (VariationID: 4296, 4288, 4327, 4328; PMID: 17689991, 20729108, 15954102, 30949558, 30764785, 29685539). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Gaucher disease based on significantly reduced levels of beta-glucosidase in patient leukocytes consistent with disease (PMID: 17689991, 30764785, 15954102). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants, in vitro functional studies, and the phenotype of individuals with the variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3_moderate, PM2_supporting, PP4 (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 252 of the GBA protein (p.Phe252Ile). This variant is present in population databases (rs381737, gnomAD 0.01%). This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 1301953, 12204005, 17689991, 29140481). This variant is also known as p.Phe213Ile. ClinVar contains an entry for this variant (Variation ID: 4301). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GBA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GBA function (PMID: 1840477). This variant disrupts the p.Phe252 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 23430543), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	Published functional studies demonstrate that this variant results in deficient beta-glucocerebrosidase activity (Kawame et al., 1991; Kim et al., 2020); Also described in past literature as p.F213I using alternate nomenclature; This variant is associated with the following publications: (PMID: 32677286, 33176831, 27802905, 15954102, 15276648, 23430543, 20301446, 30764785, 30949558, 19830760, 31637888, 30537300, 12204005, 25435509, 25875285, 29699937, 14984463, 16720474, 17689991, 1840477, 1301953, 29685539, 29140481, 20729108) -

Gaucher disease type I

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1992

- -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2018

The p.F252I variant (also known as c.754T>A, p.F213I, and c.3548T>A), located in coding exon 6 of the GBA gene, results from a T to A substitution at nucleotide position 754. The phenylalanine at codon 252 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been detected in individuals with confirmed diagnoses of Gaucher disease, in both homozygous and compound heterozygous states (Suwannarat P et al. Blood Cells Mol. Dis. Aug;39:348-52; Ortiz-Cabrera NV et al. Mol Genet Metab Rep, 2016 Dec;9:79-85; Santamaria R et al. Hum. Mutat., 2008 Jun;29:E58-67; Tang NL et al. Hum. Mutat., 2005 Jul;26:59-60; Kawame H et al. Am. J. Hum. Genet., 1991 Dec;49:1378-80; Latham TE et al. DNA Cell Biol.;10:15-21). In addition, in one study authors showed that, when this alteration was transfected into COS-1 cells, the glucosidase activity failed to increase as efficiently as normal cDNA (Kawame H et al. Am. J. Hum. Genet., 1991 Dec;49:1378-80). Of note, this alteration has also been detected in GBA pseudogene. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

Gaucher disease type II

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1992

- -

Gaucher disease type III

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.47

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.98

D;D;.;.

Eigen

Benign

0.00025

Eigen_PC

Benign

0.082

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;M;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

D;D;D;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.12

B;B;.;.

Vest4

0.82

MVP

0.93

MPC

1.4

ClinPred

0.73

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over