NM_000157.4:c.721G>A

Variant names:

• chr1-155238174-C-T
• rs409652
• NM_000157.4:c.721G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000157.4(GBA1):​c.721G>A​(p.Gly241Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,614,020 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000697594: "In vitro functional studies show that this variant leads to severely compromised enzymatic activity and/or trafficking (Grace_1997, Torralba_2001, review by Yu_2009)."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 5.20
• Publications: 54 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000697594: "In vitro functional studies show that this variant leads to severely compromised enzymatic activity and/or trafficking (Grace_1997, Torralba_2001, review by Yu_2009)."; SCV001423050: "In vitro functional studies demonstrating reduced enzyme activity in transfected COS-7 cells provide some evidence that the p.Gly241Arg variant may impact protein function." PMID:11259172, PMID:25084554; SCV000960918: Experimental studies have shown that this missense change affects GBA function (PMID: 9153297).; SCV001792358: Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 26792850)
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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, 0.889
• PP5: Variant 1-155238174-C-T is Pathogenic according to our data. Variant chr1-155238174-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 93459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.721G>A	p.Gly241Arg	missense	Exon 6 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.721G>A	p.Gly241Arg	missense	Exon 7 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.721G>A	p.Gly241Arg	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.721G>A	p.Gly241Arg	missense	Exon 6 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.721G>A	p.Gly241Arg	missense	Exon 7 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.787G>A	p.Gly263Arg	missense	Exon 8 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152134 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251482 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727242

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152134 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74316

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000291 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	1	-	not provided (7)
2	-	-	Gaucher disease (2)
1	-	-	Gaucher disease type I (1)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)
1	-	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.80
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.77	P
Vest4		0.82
MutPred		0.63		Gain of MoRF binding (P = 0.0179)
MVP		0.90
MPC		1.0
ClinPred		0.81	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.93
Mutation Taster		=2/98	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: rs409652; hg19: chr1-155207965; COSMIC: COSV59168978; COSMIC: COSV59168978;