1-155235195-C-T

Position:

• chr1-155235195-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):​c.1505G>A​(p.Arg502His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R502C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.18

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 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 chr1-155235196-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 1-155235195-C-T is Pathogenic according to our data. Variant chr1-155235195-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1505G>A	p.Arg502His	missense_variant, splice_region_variant	10/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1505G>A	p.Arg502His	missense_variant, splice_region_variant	10/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251168 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461212 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	GBA1: PM3:Strong, PS3, PM2, PP4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change affects codon 502 of the GBA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GBA protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 7694727, 17427031, 21455010, 22812582, 23588557, 24313877, 29140481). This variant is also known as IVS10-1G>A, p.Arg463His, or R463H. ClinVar contains an entry for this variant (Variation ID: 21070). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in inclusion of 12 base pairs from intron 11 (also known as intron 10) and introduces a new termination codon (PMID: 7694727). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Gaucher disease Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2019	Variant summary: GBA c.1505G>A (p.Arg502His) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. Two predict the variant creates a 3' acceptor site. At least one publication reports that this mutation resulted in altered splicing. The authors report that in the mutant allele, the normal 5'splicing site was not recognized and instead the next in intron 10 was used as splicing donor site. This resulted in a 12bp insertion in the mRNA downstream from codon 463 resulting in a new stop codon (Ohshima_1993). The variant allele was found at a frequency of 8e-06 in 251168 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Gaucher Disease ((Haverkaemper_2011, Alfonso_2007, Shehi_2011, Ohshima_1993, Moraitou_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports reduced enzymatic activity in a homozygous patient (Haverkaemper_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Gaucher disease type I Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_001005741.2(GBA):c.1505G>A(R502H, aka R463H) is classified as likely pathogenic in the context of Gaucher disease. Sources cited for classification include the following: PMID 23056756, 24278166, 22429443, 17427031, 21823541, and 21455010. Classification of NM_001005741.2(GBA):c.1505G>A(R502H, aka R463H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg502His variant in GBA has been reported in at least 8 individuals with Gaucher disease (PMID: 23332636, 17427031, 28727984, 25435509; doi:10.4172/2167-0889.1000122) and has been identified in 0.003% (1/34592) of Latino chromosomes and 0.001% (1/113456) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80356772). 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: 21070) as likely pathogenic by Counsyl. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the last base of the exon, which is part of the 5' splice region. Additional computational tools do suggest an impact to splicing. However, 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.Arg502Cys, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 4295). Additionally, the presence of this variant in combination with reported pathogenic variants and in 6 individuals with Gaucher disease increases the likelihood that the p.Arg502His variant is pathogenic (VariationID: 4290, 4288; PMID: 23332636, 17427031, 28727984, doi:10.4172/2167-0889.1000122). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on glucocerebrosidase activity being <10% of normal, consistent with disease (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 presence of another pathogenic variant at the same location, and the presence of the variant in an individual with a phenotype specific to the disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PM5, 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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.83
MutPred		0.62		Gain of ubiquitination at K505 (P = 0.0686);Gain of ubiquitination at K505 (P = 0.0686);.;.;
MVP		0.93
MPC		1.5
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.73
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -12
DS_DL_spliceai		0.38		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356772; hg19: chr1-155204986;