1-155238215-T-C

Position:

chr1-155238215-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4

The NM_000157.4(GBA1):c.680A>G(p.Asn227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,612,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N227R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.36

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:

GBA1 (HGNC:):

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-155238214-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 1-155238215-T-C is Pathogenic according to our data. Variant chr1-155238215-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155238215-T-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.221823). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.680A>G	p.Asn227Ser	missense_variant	6/11	ENST00000368373.8	NP_000148.2	P04062-1A0A068F658

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.680A>G	p.Asn227Ser	missense_variant	6/11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251308

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000582

AC:

AN:

1460174

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726484

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000552

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 227 of the GBA protein (p.Asn227Ser). This variant is present in population databases (rs364897, gnomAD 0.02%). This missense change has been observed in individuals with Gaucher disease and/or Parkinson's disease (PMID: 8829654, 21056933, 22387070, 26709268). This variant is also known as p.Asn188Ser or N188S. ClinVar contains an entry for this variant (Variation ID: 4314). 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: 15146461, 20004867, 24022302). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GBA1: PM3:Very Strong, PM2, PM5, PS3:Supporting -

Gaucher disease

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 14, 2020	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). -

Gaucher disease type I

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Oct 25, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -

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

Dec 27, 2021

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Gaucher disease type III

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.84

.;T;T;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.6

L;L;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.49

Sift

Benign

0.24

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.61

MVP

0.80

MPC

0.61

ClinPred

0.32

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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