NM_000157.4:c.1193G>T

Variant names:

• chr1-155236276-C-A
• rs74979486
• NM_000157.4:c.1193G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000157.4(GBA1):​c.1193G>T​(p.Arg398Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.19
• Publications: 13 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: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• late-onset Parkinson disease

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

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155236276-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2682534.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 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, 0.981
• PP5: Variant 1-155236276-C-A is Pathogenic according to our data. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-155236276-C-A is described in CliVar as Pathogenic. Clinvar id is 3257292.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1193G>T	p.Arg398Leu	missense_variant	Exon 8 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1193G>T	p.Arg398Leu	missense_variant	Exon 8 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PM1, PM2, PM3, PM5, PP4:Moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.
PhyloP100		5.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.83		Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);.;.;
MVP		0.95
MPC		2.0
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74979486; hg19: chr1-155206067;