VCV000029936.7 - ClinVar

NM_012084.4(GLUD2):c.1492T>G (p.Ser498Ala)

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.

(5)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012084.4(GLUD2):c.1492T>G (p.Ser498Ala)

Variation ID: 29936 Accession: VCV000029936.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq24 X: 121049176 (GRCh38) [ NCBI UCSC ] X: 120183030 (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	Apr 4, 2013	Oct 13, 2024	Sep 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012084.4:c.1492T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036216.2:p.Ser498Ala	missense
NC_000023.11:g.121049176T>G
NC_000023.10:g.120183030T>G
NG_016456.1:g.6569T>G
	P49448:p.Ser498Ala

... more HGVS ... less HGVS

Protein change

S498A

Other names

S445A

Canonical SPDI

NC_000023.11:121049175:T: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.

0.03285 (G)

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

The Genome Aggregation Database (gnomAD), exomes 0.02664

Exome Aggregation Consortium (ExAC) 0.02763

Trans-Omics for Precision Medicine (TOPMed) 0.02970

The Genome Aggregation Database (gnomAD) 0.03160

1000 Genomes Project 30x 0.03205

1000 Genomes Project 0.03285

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.03692

Links

ClinGen: CA259694 UniProtKB: P49448#VAR_048867 OMIM: 300144.0001 dbSNP: rs9697983 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 19826450 to determine the location of this allele on the current reference sequence. The nucleotide location of NM_012084.3:c.1492T>G maps to Ser498Ala, which is Ser445Ala in the mature protein after removal of the 53-aa transit peptide.

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.
GLUD2		-	-	GRCh38 GRCh38 GRCh37	40	203

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.
Parkinson disease, late-onset	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 22, 2024	RCV000022827.28
See cases	Uncertain significance (1)	criteria provided, single submitter	Nov 5, 2020	RCV002251924.2
GLUD2-related disorder	Benign (1)	no assertion criteria provided	Apr 6, 2022	RCV003974852.2

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.
Benign (Sep 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease, late-onset Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005373939.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024
Uncertain significance (Nov 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523836.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: BP4 Clinical Features: Urinary incontinence (present) , Tremor (present) , Postural instability (present) , Parkinsonian disorder (present) , Neurodevelopmental abnormality (present) , Depression (present) , Bradykinesia (present) , … (more) Urinary incontinence (present) , Tremor (present) , Postural instability (present) , Parkinsonian disorder (present) , Neurodevelopmental abnormality (present) , Depression (present) , Bradykinesia (present) , Cerebellar ataxia (present) , Abnormality of mental function (present) (less) Geographic origin: Brazil
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease, late-onset (X-linked inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048538.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The GLUD2 c.1492T>G variant has been reported previously to be a modifier of age of onset in Parkinsonism patient (Plaitakis A et al). The variant … (more) The GLUD2 c.1492T>G variant has been reported previously to be a modifier of age of onset in Parkinsonism patient (Plaitakis A et al). The variant has been submitted to ClinVar as Pathogenic based on the same publication. Experimental studies have shown that estrogen hormones inhibited the enhanced basal activity of the X-linked variant much more powerfully than that of the widely expressed hGDH1. Hence, it seems likely that, in females, estrogens may nullify the gain-of-function effects observed in male patients by blocking the overactive variant enzyme from metabolizing increased amounts of glutamate (and, in the process, damaging nigral cells). Understanding the mechanisms by which the variant hastens the commencement of PD symptoms could provide a means for retarding the development of this disorder (Plaitakis A et al). This variant is reported in gnomAD database at a frequency of 2.756% with 2188 number of hemizygotes. The allele frequency is however expected to be skewed in gnomAD. The amino acid Ser at position 498 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ser498Ala in GLUD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Considering the relative high frequency of the variant in the gnomAD, this variant has been classified as Uncertain significance. (less) Clinical Features: Mental deterioration (present) , Parkinsonian disorder (present) , Choreoathetosis (present) , Tremor (present)
Benign (Mar 01, 2010)	no assertion criteria provided Method: literature only	RECLASSIFIED - POLYMORPHISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044116.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 02, 2023	Publications: PubMed (1) PubMed: 19826450 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2023. Baltimore, Md. Comment on evidence: This variant, formerly titled PARKINSON DISEASE, AGE OF ONSET, MODIFIER, has been reclassified as a polymorphism. Hamosh (2023) noted that the S445A variant was present … (more) This variant, formerly titled PARKINSON DISEASE, AGE OF ONSET, MODIFIER, has been reclassified as a polymorphism. Hamosh (2023) noted that the S445A variant was present in 5,662 of 205,449 alleles, 71 in homozygosity and 2,188 in hemizygosity, with an allele frequency of 0.02756. Plaitakis et al. (2010) identified a c.1492T-G polymorphism in the GLUD2 gene, resulting in a ser445-to-ala (S445A) substitution in the regulatory domain, that was associated with earlier age of onset in 2 cohorts of patients with Parkinson disease (PD; 168600). Among 584 Greek patients, 1492G hemizygous males developed PD 8 to 13 years earlier than did patients with the T (p = 0.003), the G/T (p less than 0.001), or the T/T (p = 0.01) genotype. Among 224 North American patients, 1492G hemizygotes also developed PD earlier than those with other genotypes, but the mean age differences reached statistical significance only when G hemizygotes were compared to G/T heterozygotes (mean age difference: 13.1 years, p less than 0.05). Gender did not affect the age at development of PD. The frequency of the G allele was rare (3.6% in the Greek and 4.3% in the American populations). In vitro functional expression studies showed that the variant ala445 enzyme had increased basal activity and thermal stability compared to wildtype. The variant protein showed resistance to suppression by GTP, but was sensitive to inhibition by estrogen. The findings suggested an overall gain of function and explained the lack of effect in female heterozygous PD patients. Plaitakis et al. (2010) postulated that increased glutamate oxidation in the brain may increase reactive oxygen species, which would accelerate a degenerative process. (less)
Benign (Apr 06, 2022)	no assertion criteria provided Method: clinical testing	GLUD2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004787764.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

The GLUD2 c.1492T>G variant has been reported previously to be a modifier of age of onset in Parkinsonism patient (Plaitakis A et al). The variant has been submitted to ClinVar as Pathogenic based on the same publication. Experimental studies have shown that estrogen hormones inhibited the enhanced basal activity of the X-linked variant much more powerfully than that of the widely expressed hGDH1. Hence, it seems likely that, in females, estrogens may nullify the gain-of-function effects observed in male patients by blocking the overactive variant enzyme from metabolizing increased amounts of glutamate (and, in the process, damaging nigral cells). Understanding the mechanisms by which the variant hastens the commencement of PD symptoms could provide a means for retarding the development of this disorder (Plaitakis A et al). This variant is reported in gnomAD database at a frequency of 2.756% with 2188 number of hemizygotes. The allele frequency is however expected to be skewed in gnomAD. The amino acid Ser at position 498 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ser498Ala in GLUD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Considering the relative high frequency of the variant in the gnomAD, this variant has been classified as Uncertain significance.

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
Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset.	Plaitakis A	European journal of human genetics : EJHG	2010	PMID: 19826450
Hamosh, A. Personal Communication. 2023. Baltimore, Md.	-	-	-	-

Text-mined citations for rs9697983 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_012084.4(GLUD2):c.1492T>G (p.Ser498Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs9697983 ...