VCV000004293.100 - ClinVar

NM_000157.4(GBA1):c.1342G>C (p.Asp448His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(29)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_001005741.2(GBA1):c.[880T>G;1342G>C]

Identifiers

NM_000157.4(GBA1):c.1342G>C (p.Asp448His)

Variation ID: 4293 Accession: VCV000004293.100

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155235727 (GRCh38) [ NCBI UCSC ] 1: 155205518 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Oct 20, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000157.4:c.1342G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000148.2:p.Asp448His	missense
NM_001005741.3:c.1342G>C	NP_001005741.1:p.Asp448His	missense
NM_001005742.2:c.1342G>C
NM_001005742.3:c.1342G>C	NP_001005742.1:p.Asp448His	missense
NM_001171811.2:c.1081G>C	NP_001165282.1:p.Asp361His	missense
NM_001171812.2:c.1195G>C	NP_001165283.1:p.Asp399His	missense
NC_000001.11:g.155235727C>G
NC_000001.10:g.155205518C>G
NG_009783.1:g.13971G>C
NG_042867.1:g.2189C>G
	P04062:p.Asp448His

... more HGVS ... less HGVS

Protein change

D448H, D361H, D399H

Other names

D409H

Canonical SPDI

NC_000001.11:155235726:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00013

The Genome Aggregation Database (gnomAD) 0.00020

Links

ClinGen: CA221392 Genetic Testing Registry (GTR): GTR000321628 UniProtKB: P04062#VAR_003313 OMIM: 606463.0006 OMIM: 606463.0047 dbSNP: rs1064651 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GBA1		-	-	GRCh38 GRCh38 GRCh37	32	406
LOC106627981	-	-	-	GRCh38 GRCh38	-	360

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	Pathogenic (2)	criteria provided, single submitter	Apr 5, 2016	RCV000004522.17
Gaucher disease type I	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 19, 2023	RCV000004523.29
Gaucher disease type II	Pathogenic (2)	criteria provided, single submitter	Apr 5, 2016	RCV000004524.17
Gaucher disease type III	Pathogenic (1)	no assertion criteria provided	Jul 1, 2008	RCV000004525.16
Gaucher disease perinatal lethal	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 1, 2020	RCV000004526.21
Gaucher disease	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 22, 2020	RCV000055773.17
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 23, 2024	RCV000079338.51
Gaucher disease perinatal lethal Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Lewy body dementia Parkinson disease, late-onset	Pathogenic (1)	criteria provided, single submitter	Dec 16, 2021	RCV000762853.11
Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV001004114.9
not specified	Pathogenic (1)	criteria provided, single submitter	Oct 13, 2015	RCV004018557.1
Parkinson disease, late-onset	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV001836695.13
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 20, 2016)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000224864.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA Number of individuals with the variant: 16 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162845.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (Apr 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Genetic Diagnostics Department, Viafet Genomics Laboratory Accession: SCV001976454.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Publications: PubMed (6) PubMed: 33176831‚ 31130326‚ 31026225‚ 25946768‚ 19816973‚ 11992489 Comment: 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 … (more) 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). (less) Number of individuals with the variant: 1 Secondary finding: yes
Pathogenic (Apr 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Genetic Diagnostics Department, Viafet Genomics Laboratory Accession: SCV001976453.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Publications: PubMed (6) PubMed: 33176831‚ 31130326‚ 31026225‚ 25946768‚ 19816973‚ 11992489 Comment: 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 … (more) 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). (less) Number of individuals with the variant: 1 Secondary finding: yes
Pathogenic (Apr 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type II (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Genetic Diagnostics Department, Viafet Genomics Laboratory Accession: SCV001976455.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Publications: PubMed (6) PubMed: 33176831‚ 31130326‚ 31026225‚ 25946768‚ 19816973‚ 11992489 Comment: 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 … (more) 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). (less) Number of individuals with the variant: 1 Secondary finding: yes
Pathogenic (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Gaucher disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001423055.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022	Publications: PubMed (6) PubMed: 17427031‚ 18586596‚ 8213821‚ 16061944‚ 19816973‚ 11933202 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4e34ee62-adac-4732-85ac-b08a66341b05 Comment: 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 … (more) 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). (less)
Pathogenic (Aug 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329943.7 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease perinatal lethal (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003922073.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Publications: PubMed (2) PubMed: 31130326‚ 21257328 Comment: 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 … (more) 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. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Sep 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV004013958.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PS3, PM1, PM2, PP2, PP5
Pathogenic (Sep 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024190.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 23, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000964937.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 8544197‚ 11992489‚ 15146461‚ 19816973‚ 25946768‚ 8294487‚ 16293621‚ 21257328 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Parkinson disease, late-onset Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805052.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000800924.2 First in ClinVar: Feb 15, 2018 Last updated: Jun 02, 2024	Other databases https://www.ncbi.nlm.nih.gov/boo… https://www.ncbi.nlm.nih.gov/books/NBK1269/ Number of individuals with the variant: 2
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247920.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: GBA1: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM5:Supporting, PP3 Number of individuals with the variant: 4
Pathogenic (Dec 23, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Gaucher disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697581.1 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013	Publications: PubMed (1) PubMed: 16293621 Comment: 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 … (more) 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. (less)
Likely pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Gaucher disease type I Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194232.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (7) PubMed: 15146461‚ 2269438‚ 11992489‚ 16293621‚ 19816973‚ 11359469‚ 8544197 Comment: 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, … (more) 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. (less)
Pathogenic (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease perinatal lethal Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366383.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3,PS1_SUP.
Pathogenic (May 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease, late-onset Affected status: yes Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV001652792.1 First in ClinVar: May 29, 2021 Last updated: May 29, 2021
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lewy body dementia Parkinson disease, late-onset Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Gaucher disease perinatal lethal Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893213.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Aug 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV004027847.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Oculomotor apraxia (present) , Anemia (present) Age: 10-19 years Sex: female Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
Pathogenic (Oct 13, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002755388.2 First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 24126159‚ 25946768 Comment: 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 … (more) 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; Matto&scaron;ová 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. (less)
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV003921793.2 First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 31010158‚ 31130326 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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 (less)
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	Gaucher disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002086451.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Jul 01, 2008)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE IIIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024696.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (13) PubMed: 31130326‚ 8790604‚ 2502917‚ 7627184‚ 8544197‚ 10636167‚ 9040001‚ 1333717‚ 7475546‚ 1974409‚ 11148530‚ 12838552‚ 18586596 Comment on evidence: Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. … (more) Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide. The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992). Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease. Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease. Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement. Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications. Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome. Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.' Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement. Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013). Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly. (less)
Pathogenic (Jul 01, 2008)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024697.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (13) PubMed: 31130326‚ 8790604‚ 2502917‚ 7627184‚ 8544197‚ 10636167‚ 9040001‚ 1333717‚ 7475546‚ 1974409‚ 11148530‚ 12838552‚ 18586596 Comment on evidence: Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. … (more) Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide. The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992). Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease. Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease. Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement. Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications. Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome. Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.' Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement. Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013). Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly. (less)
Pathogenic (Jul 01, 2008)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE II Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024698.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (13) PubMed: 31130326‚ 8790604‚ 2502917‚ 7627184‚ 8544197‚ 10636167‚ 9040001‚ 1333717‚ 7475546‚ 1974409‚ 11148530‚ 12838552‚ 18586596 Comment on evidence: Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. … (more) Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide. The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992). Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease. Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease. Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement. Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications. Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome. Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.' Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement. Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013). Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly. (less)
Pathogenic (Jul 01, 2008)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE III Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024699.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (13) PubMed: 31130326‚ 8790604‚ 2502917‚ 7627184‚ 8544197‚ 10636167‚ 9040001‚ 1333717‚ 7475546‚ 1974409‚ 11148530‚ 12838552‚ 18586596 Comment on evidence: Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. … (more) Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide. The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992). Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease. Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease. Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement. Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications. Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome. Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.' Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement. Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013). Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly. (less)
Pathogenic (Jul 01, 2008)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, PERINATAL LETHAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024700.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (13) PubMed: 31130326‚ 8790604‚ 2502917‚ 7627184‚ 8544197‚ 10636167‚ 9040001‚ 1333717‚ 7475546‚ 1974409‚ 11148530‚ 12838552‚ 18586596 Comment on evidence: Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. … (more) Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide. The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992). Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease. Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease. Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement. Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications. Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome. Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.' Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement. Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013). Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly. (less)
not provided (-)	no classification provided Method: literature only	Gaucher disease Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086732.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 29, 2022	Publications: Bookshelf: NBK1269 Bookshelf: NBK1269
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Comment:

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).

Comment:

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).

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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; Matto&scaron;ová 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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Gaucher Disease.	Adam MP	-	2023	PMID: 20301446
The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects.	Kim YM	Orphanet journal of rare diseases	2020	PMID: 33176831
Gaucher disease type 3c: New patients with unique presentations and review of the literature.	Kurolap A	Molecular genetics and metabolism	2019	PMID: 31130326
Two siblings with Gaucher type 3c: different clinical presentations.	Karakoyun M	Journal of pediatric endocrinology & metabolism : JPEM	2019	PMID: 31026225
GBA, Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches.	Riboldi GM	Cells	2019	PMID: 31010158
Spectrum of GBA mutations in patients with Gaucher disease from Slovakia: identification of five novel mutations.	Mattošová S	The Israel Medical Association journal : IMAJ	2015	PMID: 25946768
Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease.	Li Y	Neurobiology of aging	2014	PMID: 24126159
Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models.	Xu YH	Molecular genetics and metabolism	2011	PMID: 21257328
Gaucher disease with communicating hydrocephalus and cardiac involvement.	Cindik N	Clinical cardiology	2010	PMID: 19816973
Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in glucocerebrosidase (GBA) gene.	Emre S	European journal of medical genetics	2008	PMID: 18586596
Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain.	Alfonso P	Journal of human genetics	2007	PMID: 17427031
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.	Liou B	The Journal of biological chemistry	2006	PMID: 16293621
Gaucher disease mouse models: point mutations at the acid beta-glucosidase locus combined with low-level prosaposin expression lead to disease variants.	Sun Y	Journal of lipid research	2005	PMID: 16061944
Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms.	Montfort M	Human mutation	2004	PMID: 15146461
Perinatal-lethal Gaucher disease.	Mignot C	American journal of medical genetics. Part A	2003	PMID: 12838552
Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm, and compound heterozygosity for a novel mutation (D409H/C16S).	Bodamer OA	American journal of medical genetics	2002	PMID: 11992489
The identification of eight novel glucocerebrosidase (GBA) mutations in patients with Gaucher disease.	Orvisky E	Human mutation	2002	PMID: 11933202
Severe valvular and aortic arch calcification in a patient with Gaucher's disease homozygous for the D409H mutation.	George R	Clinical genetics	2001	PMID: 11359469
A new variant neuropathic type of Gaucher's disease characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules.	Inui K	The Journal of pediatrics	2001	PMID: 11148530
Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC).	Bohlega S	Neurology	2000	PMID: 10636167
D409H/D409H genotype in Gaucher-like disease.	Uyama E	Journal of medical genetics	1997	PMID: 9040001
Unusual expression of Gaucher's disease: cardiovascular calcifications in three sibs homozygous for the D409H mutation.	Chabás A	Journal of medical genetics	1995	PMID: 8544197
Gaucher disease in Spanish patients: analysis of eight mutations.	Cormand B	Human mutation	1995	PMID: 7627184
Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype.	Abrahamov A	Lancet (London, England)	1995	PMID: 7475546
Glucocerebrosidase mutations in Gaucher disease.	Beutler E	Molecular medicine (Cambridge, Mass.)	1994	PMID: 8790604
Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression.	Grace ME	The Journal of biological chemistry	1994	PMID: 8294487
Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients.	Horowitz M	American journal of human genetics	1993	PMID: 8213821
Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells.	Uyama E	Acta neurologica Scandinavica	1992	PMID: 1333717
Prevalent and rare mutations among Gaucher patients.	Eyal N	Gene	1990	PMID: 2269438
Gaucher disease associated with a unique KpnI restriction site: identification of the amino-acid substitution.	Beutler E	Annals of human genetics	1990	PMID: 1974409
Gaucher disease: molecular heterogeneity and phenotype-genotype correlations.	Theophilus B	American journal of human genetics	1989	PMID: 2502917
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4e34ee62-adac-4732-85ac-b08a66341b05	-	-	-	-
https://www.ncbi.nlm.nih.gov/books/NBK1269/	-	-	-	-
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Text-mined citations for rs1064651 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000157.4(GBA1):c.1342G>C (p.Asp448His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1064651 ...