rs421016

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000157.4(GBA1):c.1448T>G(p.Leu483Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L483P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.95

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155235252-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 1-155235252-A-C is Pathogenic according to our data. Variant chr1-155235252-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.1448T>G	p.Leu483Arg	missense_variant	10/11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.1448T>G	p.Leu483Arg	missense_variant	10/11	1	NM_000157.4	ENSP00000357357	P1	P04062-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250058

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1461344

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L444R); This variant is associated with the following publications: (PMID: 34951095, 34867278, 24278166, 10649495, 26043810, 28003644, RiboldiGM2019[review], 31912918, 27717005, 31077260, 35885615, 38053927, 25909086, 36256599, 36334031, 35242582, 36220738, 35562809, 32613234, 35639160, 38474117, 27825739, 7981693) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 483 of the GBA protein (p.Leu483Arg). This variant is present in population databases (rs421016, gnomAD 0.006%). This missense change has been observed in individual(s) with Gaucher disease (PMID: 7981693, 27825739). This variant is also known as L444R. ClinVar contains an entry for this variant (Variation ID: 93449). 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 expected to disrupt GBA protein function with a positive predictive value of 80%. This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8294487, 15146461, 24020503, 26096741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Gaucher disease type I

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 22, 2020

The p.Leu483Arg variant in GBA has been reported in two Brazilian individuals with Gaucher disease (PMID: 27825739) and has been identified in 0.005% (1/18388) of East Asian chromosomes and 0.003% (1/34386) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs421016). 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: 93449) as likely pathogenic by GeneDx, Integrated Genetics, and the Foundation for Research In Genetics and Endocrinology, and as pathogenic 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Pro, has been reported in association with disease in ClinVar and the literature, supporting that a change at this position may not be tolerated (VariationID: 4288; PMID: 17427031, 23719189, 30662625, 28686011). The presence of this variant in combination with a reported pathogenic variant and in 2 individuals with Gaucher disease increases the likelihood that the p.Leu483Arg variant is pathogenic (VariationID: 4290, PMID: 27825739). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM3, PP3 (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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Gaucher disease type II

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Jun 29, 2018

The observed variant c.1448T>G (p.Leu483Arg) was neither found in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2. This variant was detected as a compound heterozygous along with another variant c.1448T>C (p.Leu483Pro) in exon 10 of GBA gene. The variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. Its dbSNP reference number is rs421016. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and possibly damaging by PolyPhen2. -

Gaucher disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 07, 2020

Variant summary: GBA c.1448T>G (p.Leu483Arg), also widely reported as p.Leu444Arg, results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich 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 8e-06 in 250058 control chromosomes. c.1448T>G has been reported in the literature in multiple individuals affected with Gaucher Disease (example, Basgalupp_2018, Uchiyama_1994, Smith_2016, Wilke_2019) and in association with Parkinson disease among carriers of Gaucher Disease (example, Liu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Gaucher disease type III

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093449, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004288, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.891, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Gaucher disease (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

GBA-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant is also referred to as L444R in the literature. It has been previously reported as a heterozygous and compound heterozygous change in patients with GBA-related disorders (PMID: 27825739, 7981693, 26043810, 31077260, 27717005). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (2/250058) and thus is presumed to be rare. The c.1448T>G (p.Leu483Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1448T>G (p.Leu483Arg) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

.;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.95

MutPred

0.85

Loss of stability (P = 0.027);Loss of stability (P = 0.027);.;.;

MVP

0.97

MPC

2.2

ClinPred

0.98

GERP RS

3.2

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over