rs1064651

chr1-155235727-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000157.4(GBA1):c.1342G>C(p.Asp448His) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,424 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D448V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 O:1
• Conservation: PhyloP100: 5.37

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 14 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, 2 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235726-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4294.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 1-155235727-C-G is Pathogenic according to our data. Variant chr1-155235727-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155235727-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1342G>C	p.Asp448His	missense_variant	9/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1342G>C	p.Asp448His	missense_variant	9/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152014 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 32 AN: 250360 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135308

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461294 Hom.: 0 Cov.: 32 AF XY: 0.0000922 AC XY: 67 AN XY: 726862

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152130 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13 AN XY: 74370

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000321 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease type I Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Sep 28, 2022	PS3, PM1, PM2, PP2, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 19, 2023	A Homozygous variation in exon 9 of the GAA gene that results in the amino acid substitution of Histidine for Aspartic acid at codon 448 was detected. The observed variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is disease causing by MutationTaster2, DANN and FATHMM. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostics Department, Viafet Genomics Laboratory	Apr 05, 2016	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Gaucher disease type I, II or IIIC (PMIDs: 33176831, 31130326, 31026225, 25946768, 19816973 and 11992489). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 07, 2021	0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. The different types of Gaucher disease are considered to fall within a spectrum, rather than distinct conditions, and are determined by age of disease onset and the presence and severity of neurologic function. Specific counseling about individual case prognosis is hindered by a significant overlap in the clinical features of individuals with various genotypes (OMIM, GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported, with monozygotic twins displaying a disordant phenotype (PMID: 31010158, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (38 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 TIM-barrel domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in at least ten individuals with Gaucher disease (ClinVar, PMID: 31130326). Individuals homozygous for this variant also tend to develop cardiovascular disease (GeneReviews). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000157.3(GBA):c.887G>A; p.(Arg296Gln)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_001005741.2(GBA):c.1342G>C(D448H) is classified as likely pathogenic in the context of Gaucher disease. Sources cited for classification include the following: PMID 15146461, 2269438, 11992489, 16293621, 19816973, 11359469 and 8544197. Classification of NM_001005741.2(GBA):c.1342G>C(D448H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 448 of the GBA protein (p.Asp448His). 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 missense change has been observed in individuals with GBA-related conditions (PMID: 8544197, 11992489, 15146461, 19816973, 25946768). ClinVar contains an entry for this variant (Variation ID: 4293). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 16293621, 21257328). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2021	Functional analysis of D448H found that it is associated with significantly reduced beta-glucocerebrosidase enzyme activity (Grace et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as D409H due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 19816973, 9040001, 19286695, 9061570, 10447266, 10796875, 11992489, 23588557, 16293621, 21742527, 2269438, 21700325, 15146461, 29934114, 30637984, 31709146, 31996268, 8294487, 22975760, 21745757, 24126159, 20816920, 7627184, 10360404, 21472771, 21257328, 8544197, 27312774, 26096741, 27717005, 25946768, 26887759, 29656334, 28894968, 10714667, 14578207, 8160756, 30528841, 31026225, 28393750, 31130326, 30410382, 28040394, 31216804, 31589614, 32677286, 9556036, 32618053, 33763395, 33176831, 32658388, 32714263) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GBA1: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM5:Supporting, PP3 -

Gaucher disease Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2016	Variant summary: The GBA c.1342G>C (p.Asp448His) variant, alternatively also known as D409H, involves the alteration of a conserved nucleotide, is located in Glycoside hydrolase superfamily domain (InterPro) and is predicted to be damaging by 2/4 in silico tools. This variant was found in 11/100268 control chromosomes at a frequency of 0.0001097, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant is widely reported as a pathogenic variant with consistent genotype-phenotype and functional study data. The allele frequency of this variant from a cohort of all GD patients (n=436) registered in Portugal and Spain was 28/872 (3.3%). The variant typically causes severe form of disease (i.e. GD type 3) when present in homozygous state. Another missense variant at this residue D448V is also a known pathogenic variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp448His variant in GBA has been reported in at least 33 individuals with Gaucher disease (PMID: 17427031, 8213821, 18586596, 11933202, 19816973) and has been identified in 0.020% (7/34432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1064651). 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: 4293) as likely pathogenic by Counsyl and as pathogenic by EGL Genetic Diagnostics, GeneDx, Integrated Genetics, Fulgent Genetics, Mayo Clinic Genetic Testing Laboratories, and OMIM. Animal models in mice have shown that this variant causes Gaucher disease based on visceral disease and decreased beta-glucosidase levels (PMID: 16061944). 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 likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp448Val, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 2349952, 17509920, 28223512, 2508065; Variation ID: 4294). Additionally, the homozygous occurrence of this variant in at least 23 individuals with Gaucher disease and the presence of this variant in combination with reported pathogenic variants in at least 9 individuals with Gaucher disease (VariationID: 4327, 4288, 03445; PMID: 17427031, 8213821, 18586596, 11933202, 19816973) increases the likelihood that the p.Asp448His variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the multiple occurrences of the variant in affected individuals who are homozygous or compound heterozygous with another pathogenic variant, mouse models showing the variant to be damaging, and computational tools. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2_supporting, PM5_supporting, PP3 (Richards 2015). -

Gaucher disease perinatal lethal Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.1342G>C in Exon 9 of the GBA1 gene that results in the amino acid substitution p.Asp448His was identified. The observed variant has a minor allele frequency of 0.00013 in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic [Variation ID: 4293]. The observed variant has been previously reported in patients affected with Gaucher disease (Kurolap, Alina et al., 2019). Furthermore, experimental studies have shown that this missense change affects GBA function (Xu, Y H et al., 2011). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 01, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3,PS1_SUP. -

Parkinson disease, late-onset Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2021	- -

Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostics Department, Viafet Genomics Laboratory	Apr 05, 2016	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Gaucher disease type I, II or IIIC (PMIDs: 33176831, 31130326, 31026225, 25946768, 19816973 and 11992489). -

Gaucher disease type II Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostics Department, Viafet Genomics Laboratory	Apr 05, 2016	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Gaucher disease type I, II or IIIC (PMIDs: 33176831, 31130326, 31026225, 25946768, 19816973 and 11992489). -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2015

The p.D448H pathogenic mutation (also known as c.1342G>C and p.D409H), located in coding exon 9 of the GBA gene, results from a G to C substitution at nucleotide position 1342. The aspartic acid at codon 448 is replaced by histidine, an amino acid with a few similar properties. This mutation is one of six common mutations that together account for 60-70% of Gaucher disease causing alleles in Caucasian populations and is the third most frequent mutation in Spanish patients, accounting for more than 5% of all mutated Spanish alleles (Chabas et al. J. Med. Genet. 1995;32(9):740-2; Mattošová S, et al. Isr. Med. Assoc. J. 2015;17(3):166-70). Individuals who are homozygous for this mutation generally have cardiac calcifications, ocular manifestations, and neurological disease, but variable presentation of organomegaly (Chabas et al. J. Med. Genet. 1995;32(9):740-2; Abrahamov et al. Lancet 1995;346(8981):1000-3). Both in vivo and in vitro studies have shown that this mutation demonstrates reduced enzyme activity (4- 9% of wild type) (Montfort et al. Hum. Mutat. 2004;23(6):567-75). Compound heterozygous individuals have also been reported to have Parkinson disease symptoms and cardiac manifestations along with classic Gaucher disease symptoms (Orvinsky et al. Hum. Mutat. 2002;19(4):458-9; Li Y, Neurobiol. Aging 2014 Apr; 35(4):935.e3-8). Based on the supporting evidence, p.D448H is interpreted as a disease-causing mutation. -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

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

-

- -

Gaucher disease type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Benign	0.048
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.8	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.069	T;T;T;T
Sift4G	Benign	0.091	T;T;T;T
Polyphen		0.20	B;B;.;.
Vest4		0.65
MVP		0.97
MPC		0.93
ClinPred		0.16	T
GERP RS		3.5
Varity_R		0.76
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 46

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064651; hg19: chr1-155205518; COSMIC: COSV59168989; COSMIC: COSV59168989;