1-155240629-C-T

Variant names:

• chr1-155240629-C-T
• rs104886460
• NM_000157.4:c.115+1G>A

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.115+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,613,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: GBA1 NM_000157.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 2.11

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.5, offset of 4, new splice context is: tgaGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-155240629-C-T is Pathogenic according to our data. Variant chr1-155240629-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155240629-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.115+1G>A		splice_donor_variant, intron_variant	Intron 2 of 10	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.115+1G>A		splice_donor_variant, intron_variant	Intron 2 of 10	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000758 AC: 19 AN: 250780 Hom.: 0 AF XY: 0.0000885 AC XY: 12 AN XY: 135520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1460696 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 726722

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.0000855

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Sep 06, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PS4_moderate, PVS1 -

Sep 03, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PVS1, PS4:Moderate, PM2:Supporting -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 of the GBA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individuals with Gaucher disease and/or Parkinson disease (PMID: 20816920, 23430873, 25653295, 26117366, 27682613). This variant is also known as IVS2+1. ClinVar contains an entry for this variant (Variation ID: 93445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jul 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975760, 20816920, 25653295, 25525159, 21228398, 1558964, 23430873, 21700325, 35861108, 33473340, 26689913, 26117366, 27682613, 31561936, 33176831, 36637080, 32191290, 33402667, 33301762, 34867278, 34930372, 35747619, 34308104, 35242582, 35845720, 37198191, 35639160, 36879366, 33972609, 32613234) -

Apr 15, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease Pathogenic:3 Other:1

Jan 13, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.115+1G>A variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 10649495, 23430873, 25127542) and has been identified in 0.019% (2/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886460). 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: 93445) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal 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 reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the c.115+1G>A variant is pathogenic (VariationID: 4288, 4290; PMID: 10649495, 23430873). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that the variant will cause loss-of-function and the occurrences of the variant in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 11, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GBA c.115+1G>A variant involves the alteration of a conserved intronic splice-site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant eliminates the splicing donor site, which has been confirmed in one patient using cDNA sequencing. This variant has been reported in numerous patients with Gaucher disease. This variant was found in 14/121336 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Parkinson disease, late-onset Pathogenic:3

Oct 18, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2016

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease type I Pathogenic:2

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 12204005, 25127542, 1558964, 11933202 and 20729108. Classification of NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not specified Pathogenic:1

Jan 31, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115+1G>A (also known as IVS2+1G>A) intronic pathogenic mutation from a G to A substitution one nucleotide after coding exon 2 of the GBA gene. This mutation has been reported in multiple patients with Gaucher disease, confirmed with decreased beta-glucosidase activity (Beutler E et al. Blood, 1992 Apr;79:1662-6; Yoshida S et al. Pediatr Int, 2016 Sep;58:946-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease type II Pathogenic:1

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.61	D
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.55		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886460; hg19: chr1-155210420;