rs121908311

chr1-155235823-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):c.1246G>A(p.Gly416Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,076 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G416R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 4.31

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 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 1-155235823-C-T is Pathogenic according to our data. Variant chr1-155235823-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4327.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.1246G>A	p.Gly416Ser	missense_variant	9/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1246G>A	p.Gly416Ser	missense_variant	9/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251476 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000279

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000307 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 416 of the GBA protein (p.Gly416Ser). This variant is present in population databases (rs121908311, gnomAD 0.003%). This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 8081401, 17395504, 20432762, 23430543, 25287185, 27632223, 29140481). It is commonly reported in individuals of Brazilian ancestry (PMID: 25287185). This variant is also known as p.Gly377Ser or G377S. ClinVar contains an entry for this variant (Variation ID: 4327). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8081401, 25946768, 16981045, 17395504, 23430543, 25732996, 29140481, 27717005, 20432762, 21742527, 33176831, 31467847, 27632223, 25287185, 10757640, 12595585, 22429443) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2017	- -

Gaucher disease Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly416Ser variant in GBA has been reported in at least 25 individuals with Gaucher disease (PMID: 25946768, 16981045, 23430543, 25732996, 17395504) and has been identified in 0.003% (4/129180) of European (non-Finnish) chromosomes and 0.002822% (1/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908311). 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: 4327) as pathogenic by EGL Gene Diagnostics, OMIM, and Integrated Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, the homozygous occurrence of this variant in 9 affected individuals and the presence of this variant in combination with a reported pathogenic variant in 11 individuals with Gaucher disease increases the likelihood that the p.Gly416Ser variant is pathogenic (VariationID: 4290, 4288; PMID: 25946768, 16981045, 23430543, 25732996, 17395504). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Gaucher disease based on enzyme activity of less than 1.7 nmol/h/mg protein, consistent with disease (PMID: 25946768, 16981045, 25732996). 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 in combination with other pathogenic variants in affected individuals, the phenotype of affected individuals with the variant that is specific to the disease, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4 (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2018	Variant summary: GBA c.1246G>A (p.Gly416Ser) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277220 control chromosomes (gnomAD). The variant, c.1246G>A, has been reported in the literature in multiple individuals affected with Gaucher Disease in the homozygous and compound heterozygous state. These data indicate that the variant is very likely to be associated with disease. A functional study showed the variant to have <10% activity compared to wild-type (Amaral_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Gaucher disease type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -

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

Sep 20, 2021

- -

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

-

- -

Gaucher disease type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

Pathogenic, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.87
MutPred		0.91		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MVP		0.85
MPC		1.4
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs121908311; hg19: chr1-155205614; COSMIC: COSV100516393; COSMIC: COSV100516393;