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rs421016

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_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. 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

9
8
1

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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-155235252-A-G is described in ClinVar as [Pathogenic, risk_factor]. Clinvar id is 4288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 UniProt
GBA1NM_000157.4 linkuse as main transcriptc.1448T>G p.Leu483Arg missense_variant 10/11 ENST00000368373.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GBA1ENST00000368373.8 linkuse as main transcriptc.1448T>G p.Leu483Arg missense_variant 10/111 NM_000157.4 P1P04062-1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
250058
Hom.:
0
AF XY:
0.0000148
AC XY:
2
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:
2
AN:
1461344
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
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.:
25

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
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 08, 2024This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 01, 2022Not observed at significant frequency in large population cohorts (gnomAD); 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: 24278166, 10649495, 26043810, 28003644, 7981693, 27535533, RiboldiGM2019[review], 31912918, 27717005, 27825739) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 18, 2013- -
Gaucher disease type I Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 22, 2020The 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 submitterclinical testingBaylor Genetics-- -
GBA-related disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRady 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. -
Gaucher disease type II Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsJun 29, 2018The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 07, 2020Variant 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 submitterclinical testing3billionJan 03, 2022Same 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.56
Cadd
Uncertain
26
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D;.;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.60
T
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
D
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.

Other links and lift over

dbSNP: rs421016; hg19: chr1-155205043; API