rs1553217294

chr1-155236417-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):c.1052G>C(p.Trp351Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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. W351C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.94

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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155236416-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4317.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 1-155236417-C-G is Pathogenic according to our data. Variant chr1-155236417-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496080.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.1052G>C	p.Trp351Ser	missense_variant	8/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1052G>C	p.Trp351Ser	missense_variant	8/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 15, 2020	The p.Trp351Ser variant in GBA has been reported in at least 2 individuals with Gaucher disease (PMID: 24022302, 28034821, 25326392) and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 49608) as likely pathogenic by Integrated Genetics. In vitro functional studies demonstrating that the variant results in null beta-glucosidase activity provide some evidence that the p.Trp351Ser variant may impact protein function (PMID: 24022302). However, these types of assays may not accurately represent biological function. 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 presence of this variant in combination with a reported pathogenic variant and in at least one individual with Gaucher disease slightly increases the likelihood that the p.Trp351Ser variant is pathogenic (VariationID: 4288; PMID: 28034821, 24022302). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_moderate, PM3_supporting, PP3 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2016	Variant summary: The GBA c.1052G>C (p.Trp351Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is located in the catalytic domain and/or the TIM-barrel domain (InterPro). This variant was absent in 121240 control chromosomes, but has been reported by two studies in the literature (Stirnemann_2012, Malini_2013). In a patient reported by Malini_2013, it was found in compound heterozygous state with another likely pathogenic variant, p.Leu483Pro, in a patient with type 1 Gaucher disease. By an in vitro functional study, this variant was found to abrogate the enzymatic activity (Malini_2013). Additionally, one reputable database (HGMD) has classified it as a disease-causing mutation. Taken together, this variant is classified as Likely Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	31
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-13	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.73		Loss of stability (P = 0.1114);Loss of stability (P = 0.1114);.;.;
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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: rs1553217294; hg19: chr1-155206208;