rs387906315

chr1-155240660-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000157.4(GBA1):c.84_85insG(p.Leu29AlafsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 152,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L28L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 0.516

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 252 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-155240660-G-GC is Pathogenic according to our data. Variant chr1-155240660-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 4302.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.84_85insG	p.Leu29AlafsTer18	frameshift_variant	2/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.84_85insG	p.Leu29AlafsTer18	frameshift_variant	2/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250996 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000287 AC: 42 AN: 1461428 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74308

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2022	Identified in the heterozygous state in patients with Parkinson disease, but also in control individuals (Ruskey et al., 2019; Gan-Or et al., 2015; Choi et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10796875, 21228398, 25653295, 26096741, 22975760, 27717005, 25946768, 21700325, 29842932, 8889578, 7789963, 8516282, 34017912, 29471591, 17875915, 21742527, 1961718) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Leu29Alafs*18) in the GBA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). This variant is present in population databases (rs387906315, gnomAD 0.09%). This premature translational stop signal has been observed in individuals with Gaucher disease and/or Parkinson's disease and dementia with Lewy bodies (PMID: 1961718, 21742527, 25653295, 25933391, 26096741, 27717005). This variant is also known as 84GG. ClinVar contains an entry for this variant (Variation ID: 4302). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2014	- -

Gaucher disease Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Leu29AlafsTer18 variant in GBA has been reported in at least 70 individuals with Gaucher disease (PMID: 10777718, 19513999) and has been identified in 0.077% (8/10370) of Ashkenazi Jewish chromosomes, 0.006% (2/35440) of Latino chromosomes, and 0.002% (2/128886) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906315). 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: 4302) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, and OMIM. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 29 and leads to a premature termination codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GBA gene is an established disease mechanism in autosomal recessive Gaucher disease. The presence of this variant in combination with a reported pathogenic variant and in 70 individuals with Gaucher disease increases the likelihood that the p.Leu29AlafsTer18 variant is pathogenic (VariationID: 4290; PMID: 10777718, 19513999). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that it causes loss of function and the presence of the variant in combination with a known pathogenic variant. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PM2_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2017	Variant summary: The GBA c.84dupG (p.Leu29Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent GBA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and other labs/reputable databases in ClinVar (e.g. c.487delG, c.1029delT, c.1265_1319del55, etc.). This variant was found in 6/121380 control chromosomes from ExAC at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant is reported as one of the common pathogenic variants in literature found especially in Ashkenazi Jews population (Beutler_1991, Koprivica_2000, Brautbar_2003, Giraldo_2011). Functional data are consistent with predicted outcome of this variant because no translation product could be detected in an in vitro translation system and little or no enzyme antigen attributed to this allele could be found in cell lines from patients (Beutler_1991). Three clinical labs (via ClinVar) and a reputable database have classified this variant as pathogenic. Taken together, this variant has been classified as a pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Gaucher disease type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_001005741.2(GBA):c.84dupG(L29Afs*18, aka p.L29Afs*18) is classified as pathogenic in the context of Gaucher disease and may be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 21742527, 8487270, 1961718, 1348297 and 8432537. Classification of NM_001005741.2(GBA):c.84dupG(L29Afs*18, aka p.L29Afs*18) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

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Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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Computational scores

Source: dbNSFP v4.3

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: rs387906315; hg19: chr1-155210451;