rs77829017

chr1-155239939-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):c.254G>A(p.Gly85Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.45

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-155239939-C-T is Pathogenic according to our data. Variant chr1-155239939-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.254G>A	p.Gly85Glu	missense_variant	3/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.254G>A	p.Gly85Glu	missense_variant	3/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251318 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2017	Variant summary: The GBA c.254G>A (p.Gly85Glu) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/246122 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients diagnosed with Gaucher disease Type 1, as a homozygous and compound heterozygous allele, and is a common Gaucher disease allele in East Asian populations (Jeong_2011). One study reported the GBA enzyme activity levels in compound heterozygous patients to be ~10-20% of normal levels (Choi_2015). In addition, multiple reputable databases/clinical diagnostic laboratory have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 15, 2020	The p.Gly85Glu variant in GBA has been reported in at least 15 Korean individuals with Gaucher disease (PMID: 22375149, 20729108, 30764785) and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77829017). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 4296) as pathogenic by OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Gaucher disease based on low glucocerebrosidase activity consistent with disease (PMID: 22375149, 30764785). The presence of this variant in 2 affected homozygotes and in combination with reported pathogenic variants in 9 individuals with Gaucher disease increases the likelihood that the p.Gly85Glu variant is pathogenic (VariationID: 4288, 4301, 65570, 4328, 4297; PMID: 22375149, 20729108, 30764785). 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 homozygotes and compound heterozygotes in combination with pathogenic variants and the phenotype of patients with the variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Gaucher disease type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.87		Loss of methylation at R86 (P = 0.0438);Loss of methylation at R86 (P = 0.0438);Loss of methylation at R86 (P = 0.0438);
MVP		0.95
MPC		0.20
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.82
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs77829017; hg19: chr1-155209730;