rs364897

chr1-155238215-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000157.4(GBA1):c.680A>G(p.Asn227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,612,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N227R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 3.36

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 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-155238214-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-155238215-T-C is Pathogenic according to our data. Variant chr1-155238215-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155238215-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.221823).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.680A>G	p.Asn227Ser	missense_variant	6/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.680A>G	p.Asn227Ser	missense_variant	6/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152108 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251308 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135828

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1460174 Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 726484

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152226 Hom.: 0 Cov.: 30 AF XY: 0.0000672 AC XY: 5 AN XY: 74420

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000552 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GBA1: PM3:Very Strong, PM2, PM5, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 227 of the GBA protein (p.Asn227Ser). This variant is present in population databases (rs364897, gnomAD 0.02%). This missense change has been observed in individuals with Gaucher disease and/or Parkinson's disease (PMID: 8829654, 21056933, 22387070, 26709268). This variant is also known as p.Asn188Ser or N188S. ClinVar contains an entry for this variant (Variation ID: 4314). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GBA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GBA function (PMID: 15146461, 20004867, 24022302). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2017	- -

Gaucher disease Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	Variant summary: GBA c.680A>G (p.Asn227Ser) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251308 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (7.2e-05 vs 0.005), allowing no conclusion about variant significance. The variant has been reported in the homozygous and compound heterozygous genotypes in numerous publications of patients with Gaucher Disease and has also been reported in patients in cis with a second variant E326K (example, Alfonso_2007, Biegstraaten_2011, Erdos_2007, Jeong_2011, Tajima_2010). The variant has been shown to result in moderate reductions in enzyme activity via various expression systems (~25%-66% residual activity; Malini_2014, Tajima_2010, Montfort_2004). While the E326K variant does not have a significant effect on enzyme activity in these studies (and has not been observed in GD patients on its own), the addition of the variant of interest resulted in greater effects on activity (completely inactive in one study, 25% residual activity in a second study). Despite the high residual activity reported in these studies, patients with a rare myoclonic epilepsy phenoptype have also been reported in association with the variant (Kowarz_2005). Additionally, in a pair of monozygotic twins, both homozygous for the variant and both having <20% glucocerebrosidase activity in leukocytes, highly discordant manifestations of Gaucher disease were observed: one sister had severe visceral involvment, epilepsy and cerebellar syndrome, while the other had no symptoms of Gaucher disease (Biegstraaten_2011). This report indicates incomplete penetrance and/or variable expressivity, even in individuals having near identical genetic sequence. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these submitters cites overlapping evidences utilized in the context of this evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was re-classified as pathogenic mindful of the caveats of penetrance and expressivity summarized above. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 14, 2020	The p.Asn227Ser variant in GBA has been reported in at least 28 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 20004867, 12595585, 8829654, 20729108, 17395504, 30497978, 27872820, 24022302, 30382391, 15146461, 16086325, 21056933), has been identified in 0.020% (5/24920) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs364897). 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 pathogenic by EGL Genetic Diagnostics and OMIM, and likely pathogenic by Integrated Genetics in ClinVar (Variation ID: 4314). Twins that are monozygous and homozygous for this variant show different clinical presentations, suggesting that there may be incomplete penetrance or variable expressivity associated with this variant. In vitro functional studies provide some evidence that the p.Asn227Ser variant may slightly impact protein function either alone or in cis with another pathogenic variant (PMID: 20004867, 26743617, 27865684, 30497978, 15146461, 24022302). However, these types of assays may not accurately represent biological function. The presence of this variant in 3 affected homozygotes and in combination with at least 7 reported pathogenic variants and in 14 individuals with Gaucher disease increases the likelihood that the p.Asn227Ser variant is pathogenic (PMID: 8829654, 21056933, 12595585, 8829654, 20729108, 30497978, 27872820, 16086325; VariationID: 4302, 4288, 93459, 4290, 99352, 76478, 4297). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Gaucher disease based on low glucocerebrosidase activity consistent with Gaucher disease (PMID: 30382391, 16086325, 21056933). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner with incomplete penetrance or variable expressivity based on multiple occurrences with pathogenic GBA variants in individuals with Gaucher Disease. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PM2_supporting, PS3_supporting, PP4, PP1 (Richards 2015). -

Gaucher disease type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Oct 25, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -

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

Dec 27, 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

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	19
Dann	Benign	0.46
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.61
MVP		0.80
MPC		0.61
ClinPred		0.32	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.90

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: rs364897; hg19: chr1-155208006; COSMIC: COSV105891369; COSMIC: COSV105891369;