rs75822236

Variant names:

• chr1-155235002-C-T
• rs75822236
• NM_000157.4:c.1604G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4

The NM_000157.4(GBA1):​c.1604G>A​(p.Arg535His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000966890: "In vitro functional studies support an impact on protein function (Liou 2006, Choy 1996)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R535C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 11)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 0.830
• Publications: 62 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000966890: "In vitro functional studies support an impact on protein function (Liou 2006, Choy 1996)."; SCV001422767: "In vitro functional studies showing the variant to result in significantly reduced CRIM specific activity provide some evidence that the p.Arg535His variant may slightly impact protein function (PMID: 16293621)."; SCV000930789: Experimental studies have shown that this missense change affects GBA function (PMID: 16293621).; SCV001803479: Published functional studies demonstrate that this variant had little or no catalytic activity (Liou et al., 2006); SCV002755628: In another study which characterized basic kinetic, stability, and activator response properties of this alteration in an in vitro environment, authors concluded that this alteration has little, if any, in vitro catalytic activity (Liou B et al. J. Biol. Chem. 2006; 281(7):4242-53).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235003-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 242383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant 1-155235002-C-T is Pathogenic according to our data. Variant chr1-155235002-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32971787). . Strength limited to SUPPORTING due to the PP5.

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.1604G>A	p.Arg535His	missense	Exon 11 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1604G>A	p.Arg535His	missense	Exon 12 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1604G>A	p.Arg535His	missense	Exon 12 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.1604G>A	p.Arg535His	missense	Exon 11 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1604G>A	p.Arg535His	missense	Exon 12 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1670G>A	p.Arg557His	missense	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0000553 AC: 5 AN: 90450 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00123

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000223

Gnomad OTH AF: 0.000931

GnomAD2 exomes AF: 0.000182 AC: 31 AN: 170078 AF XY: 0.000155

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00254

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 80 AN: 680418 Hom.: 0 Cov.: 9 AF XY: 0.0000993 AC XY: 35 AN XY: 352508

African (AFR) AF: 0.000110 AC: 2 AN: 18106

American (AMR) AF: 0.000183 AC: 6 AN: 32842

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 45 AN: 18450

East Asian (EAS) AF: 0.0000311 AC: 1 AN: 32120

South Asian (SAS) AF: 0.0000677 AC: 4 AN: 59106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2624

European-Non Finnish (NFE) AF: 0.0000340 AC: 15 AN: 441020

Other (OTH) AF: 0.000206 AC: 7 AN: 33952

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000553 AC: 5 AN: 90450 Hom.: 0 Cov.: 11 AF XY: 0.0000243 AC XY: 1 AN XY: 41182

African (AFR) AF: 0.00 AC: 0 AN: 22112

American (AMR) AF: 0.00 AC: 0 AN: 7908

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 3 AN: 2446

East Asian (EAS) AF: 0.00 AC: 0 AN: 3256

South Asian (SAS) AF: 0.00 AC: 0 AN: 2236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000223 AC: 1 AN: 44792

Other (OTH) AF: 0.000931 AC: 1 AN: 1074

Alfa AF: 0.000360 Hom.: 0

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000859 AC: 10

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Gaucher disease type I (7)
5	-	-	not provided (5)
3	-	-	Gaucher disease (4)
1	-	-	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 (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	-	-	not specified (1)
1	-	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.83
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.57
Sift	Benign	0.052	T
Sift4G	Benign	0.18	T
Polyphen		0.49	P
Vest4		0.68
MVP		0.79
MPC		0.99
ClinPred		0.018	T
GERP RS		1.2
Varity_R		0.13
gMVP		0.67
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs75822236; hg19: chr1-155204793;