1-155235252-A-G

Variant names:

• chr1-155235252-A-G
• rs421016
• NM_000157.4:c.1448T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM5 PP2 PP3 PP5_Very_Strong BP4

The NM_000157.4(GBA1):​c.1448T>C​(p.Leu483Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (★★). ClinVar reports functional evidence for this variant: "SCV002058438: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:15146461, 28969384" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L483R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:44 O:5
• Conservation: PhyloP100: 7.95
• Publications: 1188 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002058438: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:15146461, 28969384; SCV002073104: Experimental studies have shown that this missense change affects GBA function (Migdalska-Richards A, et. al., 2017).; SCV004100811: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; PMID: 2880291; SCV005419279: "functional in vivo abd in vitro studies have shown that the variant impairs the activity" (PMID: 28969384, 24022302, 8294487); SCV000697583: Functional studies report the variant effect results in decreasing GBA enzyme activity in transfected cells (Alfonso__2004, Malini_2013).; SCV001422763: "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 affected individuals and in combination with other pathogenic variants, functional studies, and the phenotype of individuals with this variant being highly specific for Gaucher disease."; SCV002107096: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8294487; 15146461; 30285649; 28969384) - PS3_moderate."; SCV002768544: "In vitro assays demonstrated 13% residual enzymatic activity." PMID:24022302; SCV000491300: Published functional studies demonstrate a damaging effect indicating that this variant is poorly activated by phosphatidylserine, is unstable and has residual enzyme activity of 5-10% of wild type (Grace et al., 1994; Malini et al., 2014).; SCV000964136: Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 15146461, 24020503).; SCV002049503: Functional studies in both patient-derived cells and cultured cell lines demonstrate enzymatic activity of the variant protein at <10% of normal (Grace 1994, Ivanova 2018, Montfort 2004). PMID: 8294487. PMID: 30662625. PMID: 15146461.; SCV007107388: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV004120381: Beta-glucosidase residual activity in individuals homozygous and compound heterozygous for this variant is reported below <10% of normal, consistent with Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625; Tammachote et al. 2013. PubMed ID: 23719189).; SCV002755393: Functional analysis of the L483P mutant protein expressed in HEK293 cells revealed that residual GBA activity was 13% as compared to wild-type (Malini, 2014).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235252-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 93449.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.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-155235252-A-G is Pathogenic according to our data. Variant chr1-155235252-A-G is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 4288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19879305). . 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.1448T>C	p.Leu483Pro	missense	Exon 10 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1448T>C	p.Leu483Pro	missense	Exon 11 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1448T>C	p.Leu483Pro	missense	Exon 11 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.1448T>C	p.Leu483Pro	missense	Exon 10 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1448T>C	p.Leu483Pro	missense	Exon 11 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1514T>C	p.Leu505Pro	missense	Exon 12 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151964 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00130 AC: 324 AN: 250058 AF XY: 0.00124

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000842 AC: 123 AN: 1460902 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 726764

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

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.000112 AC: 5 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26118

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39658

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86214

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53362

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111332

Other (OTH) AF: 0.000149 AC: 9 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000237 AC: 36 AN: 152080 Hom.: 0 Cov.: 25 AF XY: 0.000256 AC XY: 19 AN XY: 74322

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

African (AFR) AF: 0.000434 AC: 18 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00253 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00315 AC: 383

ClinVar

ClinVar submissions

Significance: Pathogenic; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Gaucher disease type I (10)
9	-	-	not provided (9)
7	-	-	Gaucher disease (8)
5	-	-	Gaucher disease type II (5)
3	-	-	Gaucher disease type III (3)
2	-	-	Gaucher disease perinatal lethal (3)
2	-	-	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 (2)
2	-	-	Parkinson disease, late-onset (3)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)
1	-	-	GBA1-related disorder (1)
1	-	-	Lewy body dementia (1)
1	-	-	not specified (1)
-	-	-	Dementia, Lewy body, susceptibility to (1)
-	-	-	Movement disorder;C0234379:Resting tremor;C0242422:Parkinsonian disorder;C0749379:Thoracolumbar scoliosis;C0813217:Hypomimic face (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.20	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.035	D
Polyphen		0.94	P
Vest4		0.96
MVP		0.94
MPC		2.3
ClinPred		0.10	T
GERP RS		3.2
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	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: rs421016; hg19: chr1-155205043;