1-155235007-C-T

Position:

• chr1-155235007-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_000157.4(GBA1):​c.1599G>A​(p.Trp533Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 11)
• Consequence: GBA1 NM_000157.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PP5: Variant 1-155235007-C-T is Pathogenic according to our data. Variant chr1-155235007-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 917862.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1599G>A	p.Trp533Ter	stop_gained	11/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1599G>A	p.Trp533Ter	stop_gained	11/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD4 exome Cov.: 9

GnomAD4 genome Cov.: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Gaucher disease type I Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University

Jun 04, 2020

The c.1599G>A variant in GBA was absent from large population and our in-house database. This variant segregated with the non-neuronopathic Gaucher disease. The glucocerbrosidase enzyme activity was deficient. -

Gaucher disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 15, 2023

Variant summary: GBA c.1599G>A (p.Trp533X) results in a premature termination codon. While the variant is not expected to undergo nonsense-mediated decay, variants downstream of this position have been classified as pathogenic by our laboratory (p.Arg535Cys, p.Arg535His). The variant was absent in 176860 control chromosomes. c.1599G>A has been reported in the literature in compound heterozygous indivudals affected with Gaucher Disease including one neonatal case who carried a VUS in cis and a pathogenic variant in trans (Phetthong_2021, Lecourt_2013). At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Lecourt_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23935976, 34930372). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Benign	0.96
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	0.91	D;D;D;D;D
Vest4		0.69
GERP RS		3.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1671655923; hg19: chr1-155204798;