rs398123530

Variant names:

• chr1-155238597-G-A
• rs398123530
• NM_000157.4:c.508C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):​c.508C>T​(p.Arg170Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,461,660 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.79
• Publications: 19 publications found

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]

GBA1 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000157.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155238596-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 813341.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-155238597-G-A is Pathogenic according to our data. Variant chr1-155238597-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 93453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.508C>T	p.Arg170Cys	missense_variant	Exon 5 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.508C>T	p.Arg170Cys	missense_variant	Exon 5 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151786 Hom.: 0 Cov.: 29

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251172 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461660 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151786 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74122

African (AFR) AF: 0.00 AC: 0 AN: 41222

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2082

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 16, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting -

Gaucher disease Pathogenic:2

Apr 26, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBA c.508C>T (p.Arg170Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) 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 4e-06 in 251172 control chromosomes. c.508C>T has been reported in the literature as homozygous or compound heterozygous genotypes in multiple individuals affected with Gaucher Disease (example, Miano_2020, Costa_2020, D'Amore_2021, Filocamo_2002, Schuler_2016). These data indicate that the variant is very likely to be associated with disease. No direct experimental evidence demonstrating an impact on protein function has been ascertained in the context of this evaluation although at-least one study reports non-primary evidence supporting a diagnosis of Gaucher Disease by enzyme analysis in a preterm infant homozygous for this variant (Schuler_2016). The following publications have been ascertained in the context of this evaluation (PMID: 31816052, 34649574, 12204005, 32702516, 27922757). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 14, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg170Cys variant in GBA has been reported in at least 10 individuals with Gaucher disease (PMID: 29602947, 23430543, 27008851, 17427031, 20946052, 27922757, 22623374, 20880730) and has been identified in 0.005% (1/21648) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123530). 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 as pathogenic by EGL Genetic Diagnostics (VariationID: 93453). 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 phenotype of 2 individuals homozygous or compound heterozygous for this variant is highly specific for Gaucher disease based on null or very low beta-glucosidase activity levels consistent with disease (PMID: 22623374, 29602947). The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 6 individuals with Gaucher disease increases the likelihood that the p.Arg170Cys variant is pathogenic (VariationID: 65570, 4290, 4297, 4288; PMID: 29602947, 23430543, 27008851, 17427031, 20946052, 27922757, 22623374). 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 compound heterozygotes with pathogenic variants, the low frequency of the variant in the general population, and the phenotype of patients with the variant being highly specific for the gene. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;D;.;.
Eigen	Benign	0.0091
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;.;.
PhyloP100		4.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.83
MutPred		0.89		Loss of phosphorylation at T173 (P = 0.0923);Loss of phosphorylation at T173 (P = 0.0923);.;.;
MVP		0.92
MPC		1.3
ClinPred		0.91	D
GERP RS		2.6
Varity_R		0.88
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398123530; hg19: chr1-155208388;