dbSNP rs758447515: GBA1:p.Ser146Leu (chr1-155239633-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000157.4(GBA1):c.437C>T(p.Ser146Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,884 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: 0.000011 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 5.03

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant 1-155239633-G-A is Pathogenic according to our data. Variant chr1-155239633-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197702.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.437C>T	p.Ser146Leu	missense_variant	Exon 4 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.437C>T	p.Ser146Leu	missense_variant	Exon 4 of 11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251456

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 02, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in the heterozygous state in an individual with Parkinson disease (Pakarulrazy et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27836528, 27789132, 9516376, 24262167, 32165122, 10744424, 12970647, 25567624, 15329082, 27816428, 23056756, 10649495, 34072542, 27872820, 9554454, 30949558, Pakarulrazy2020[article], 22247978, 32658388, 33473340) -

Sep 05, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Pathogenic:1

Jul 10, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S146L variant (also known as c.437C>T and S107L), located in coding exon 4 of the GBA gene, results from a C to T substitution at nucleotide position 437. The serine at codon 146 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in conjunction with a pathogenic GBA alteration in individuals with type 1 and type 2 Gaucher disease; however, phase of the alterations was not confirmed (Demina A et al. Acta Haematol., 1998;99:80-2; Machaczka M et al. Ups. J. Med. Sci., 2012 Mar;117:28-34; Ortiz-Cabrera NV et al. Mol Genet Metab Rep, 2016 Dec;9:79-85). In our internal cohort, this variant was detected in an obligate carrier with a history of two affected pregnancies with the perinatal-lethal form of Gaucher disease. This amino acid position is not 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 I

Pathogenic:1

Feb 23, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease

Pathogenic:1

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.Ser146Leu variant in GBA has been reported in 7 individuals with Gaucher Disease (PMID: 15329082, 30949558; doi:10.4172/2167-0889.1000122) and has been identified in 0.006% (7/113742) of European (non-Finnish) chromosomes and 0.006% (1/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758447515). 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: 197702) as a VUS by EGL Genetic Diagnostics. 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 in 6 individuals with Gaucher Disease increases the likelihood that the p.Ser146Leu variant is pathogenic (VariationID: 4290; PMID: 30949558; doi:10.4172/2167-0889.1000122). The p.Ser146Leu variant is located in the catalytic domain of GBA, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 30949558). The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher Disease based on low glucocerebrosidase activity consistent with disease (PMID: 15329082; doi:10.4172/2167-0889.1000122). 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, the variant being located in a functional domain, and the phenotype of an individual with the variant being highly specific for Gaucher Disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PM1, PP3, PP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.0

M;M;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.80

MVP

0.95

MPC

1.6

ClinPred

0.80

GERP RS

3.3

Varity_R

0.75

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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