rs61748906

Variant names:

• chr1-155238228-A-G
• rs61748906
• NM_000157.4:c.667T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PP2 PP3_Strong PP5

The NM_000157.4(GBA1):​c.667T>C​(p.Trp223Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,912 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005080113: Functional studies found that W223R is associated with significantly reduced enzyme activity (PMID:10757640)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W223C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 8.10
• Publications: 23 publications found

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: Genomics England PanelApp, Laboratory for Molecular Medicine, G2P
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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: Genomics England PanelApp, Orphanet
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005080113: Functional studies found that W223R is associated with significantly reduced enzyme activity (PMID: 10757640);; SCV000697591: This was confirmed by functional studies showing abrogated Beta-glucosidase catalytic activity (0.0004 total units of specific activity per cross-reacting immunologic material (CRIM SA) (vs. 1 in control) (Amaral_2000, Awad_2015).; SCV001422957: "In vitro functional studies demonstrating very low glucocerebrosidase activity in mutant hiPSC macrophages provide some evidence that the p.Trw223Arg variant may impact protein function." PMID:24801745; SCV003570750: Expression studies in Sf9 cells showed very low activity and an essentially inactive protein (Amaral, 2000). Human induced pluripotent stem cells from fibroblasts of an affected patient with this alteration and a second alteration showed low levels of beta-glucocerebrosidase activity and widespread lysosomal depletion and dysfunction (Panicker, 2014; Awad, 2015).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 type I, Gaucher disease type III, Gaucher disease type II, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease perinatal lethal, Gaucher disease, Parkinson disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-155238228-A-G is Pathogenic according to our data. Variant chr1-155238228-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93457.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_000157.4	MANE Select	c.667T>C	p.Trp223Arg	missense	Exon 6 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.667T>C	p.Trp223Arg	missense	Exon 7 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.667T>C	p.Trp223Arg	missense	Exon 7 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.667T>C	p.Trp223Arg	missense	Exon 6 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.667T>C	p.Trp223Arg	missense	Exon 7 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.733T>C	p.Trp245Arg	missense	Exon 8 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251106 AF XY: 0.00000737

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461736 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727136

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111948

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000281524), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 30 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	not provided (5)
3	-	-	Gaucher disease (3)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1961835:Gaucher disease type I (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Benign	0.78
DEOGEN2	Pathogenic	0.99	D
Eigen	Benign	0.017
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.074	T
Polyphen		0.99	D
Vest4		0.95
MutPred		0.90		Gain of disorder (P = 0.0057)
MVP		0.94
MPC		2.4
ClinPred		0.83	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61748906; hg19: chr1-155208019;