rs121908314

Variant names:

• chr1-155235841-G-C
• rs121908314
• NM_000157.4:c.1228C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000157.4(GBA1):​c.1228C>G​(p.Leu410Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.91
• Publications: 5 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 10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• 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 perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 1-155235841-G-C is Pathogenic according to our data. Variant chr1-155235841-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4332.Status of the report is no_assertion_criteria_provided, 0 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.1228C>G	p.Leu410Val	missense	Exon 9 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1228C>G	p.Leu410Val	missense	Exon 10 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1228C>G	p.Leu410Val	missense	Exon 10 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.1228C>G	p.Leu410Val	missense	Exon 9 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1228C>G	p.Leu410Val	missense	Exon 10 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1294C>G	p.Leu432Val	missense	Exon 11 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Gaucher disease type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.049	D
Polyphen		0.96	D
Vest4		0.91
MutPred		0.82		Loss of helix (P = 0.1299)
MVP		0.95
MPC		1.5
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908314; hg19: chr1-155205632;