rs758447515

Variant names:

• chr1-155239633-G-A
• rs758447515
• NM_000157.4:c.437C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-155239633-G-A
• chr1-155239633-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP2 PP3_Moderate PP5

The NM_000157.4(GBA1):​c.437C>T​(p.Ser146Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,884 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.03
• Publications: 13 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4
• 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, 0.924
• PP5: Variant 1-155239633-G-A is Pathogenic according to our data. Variant chr1-155239633-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197702.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.437C>T	p.Ser146Leu	missense_variant	Exon 4 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.437C>T	p.Ser146Leu	missense_variant	Exon 4 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251456 AF XY: 0.0000441

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000203 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Mar 02, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in the heterozygous state in an individual with Parkinson disease (Pakarulrazy et al., 2020); 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: 27836528, 27789132, 9516376, 24262167, 32165122, 10744424, 12970647, 25567624, 15329082, 27816428, 23056756, 10649495, 34072542, 27872820, 9554454, 30949558, Pakarulrazy2020[article], 22247978, 32658388, 33473340) -

Sep 05, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Jul 10, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S146L variant (also known as c.437C>T and S107L), located in coding exon 4 of the GBA gene, results from a C to T substitution at nucleotide position 437. The serine at codon 146 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in conjunction with a pathogenic GBA alteration in individuals with type 1 and type 2 Gaucher disease; however, phase of the alterations was not confirmed (Demina A et al. Acta Haematol., 1998;99:80-2; Machaczka M et al. Ups. J. Med. Sci., 2012 Mar;117:28-34; Ortiz-Cabrera NV et al. Mol Genet Metab Rep, 2016 Dec;9:79-85). In our internal cohort, this variant was detected in an obligate carrier with a history of two affected pregnancies with the perinatal-lethal form of Gaucher disease. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Gaucher disease type I Pathogenic:1

Feb 23, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease Pathogenic: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 p.Ser146Leu variant in GBA has been reported in 7 individuals with Gaucher Disease (PMID: 15329082, 30949558; doi:10.4172/2167-0889.1000122) and has been identified in 0.006% (7/113742) of European (non-Finnish) chromosomes and 0.006% (1/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758447515). 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: 197702) as a VUS by EGL Genetic Diagnostics. 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 reported pathogenic variants in 6 individuals with Gaucher Disease increases the likelihood that the p.Ser146Leu variant is pathogenic (VariationID: 4290; PMID: 30949558; doi:10.4172/2167-0889.1000122). The p.Ser146Leu variant is located in the catalytic domain of GBA, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 30949558). The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher Disease based on low glucocerebrosidase activity consistent with disease (PMID: 15329082; doi:10.4172/2167-0889.1000122). 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 combination with other pathogenic variants, the variant being located in a functional domain, and the phenotype of an individual with the variant being highly specific for Gaucher Disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PM1, PP3, PP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.0	M;M;.
PhyloP100		5.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.80
MVP		0.95
MPC		1.6
ClinPred		0.80	D
GERP RS		3.3
Varity_R		0.75
gMVP		0.83
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs758447515; hg19: chr1-155209424; COSMIC: COSV59169412; COSMIC: COSV59169412;