ClinVar Genomic variation as it relates to human health
NM_000170.3(GLDC):c.482A>G (p.Tyr161Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000170.3(GLDC):c.482A>G (p.Tyr161Cys)
Variation ID: 56098 Accession: VCV000056098.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p24.1 9: 6610345 (GRCh38) [ NCBI UCSC ] 9: 6610345 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 24, 2013 Jun 17, 2024 Dec 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000170.3:c.482A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000161.2:p.Tyr161Cys missense NC_000009.12:g.6610345T>C NC_000009.11:g.6610345T>C NG_016397.1:g.40348A>G LRG_643:g.40348A>G LRG_643t1:c.482A>G LRG_643p1:p.Tyr161Cys - Protein change
- Y161C
- Other names
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- Canonical SPDI
- NC_000009.12:6610344:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GLDC | - | - |
GRCh38 GRCh37 |
2397 | 2594 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 18, 2023 | RCV000049507.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2018 | RCV000999135.18 | |
GLDC-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2023 | RCV003974936.1 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(Jun 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020486.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: GLDC c.482A>G (p.Tyr161Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: GLDC c.482A>G (p.Tyr161Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251282 control chromosomes (gnomAD). c.482A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Korman_2006, Swanson_2015, Coughlin_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27362913, 16404748, 26179960). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001591333.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the GLDC protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the GLDC protein (p.Tyr161Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 16404748, 27362813; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLDC protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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GLDC-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004789586.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GLDC c.482A>G variant is predicted to result in the amino acid substitution p.Tyr161Cys. This variant was reported in the homozygous state in two siblings … (more)
The GLDC c.482A>G variant is predicted to result in the amino acid substitution p.Tyr161Cys. This variant was reported in the homozygous state in two siblings with non-ketotic hyperglycinaemia (NKH). Patient 1 had CSF and plasma glycine levels consistent with severe neonatal onset NKH. Glycine cleavage enzyme system (GCS) activity in placental tissue of patient 2 was 2.6% of controls (Korman et al. 2006. PubMed ID: 16404748). Additional patients with a clinical suspicion of NKH have been reported to be homozygous or compound heterozygous for this variant and a second pathogenic GLDC variant (Coughlin et al. 2017. PubMed ID: 27362913, Supplemental Table 1). This variant has not been reported in a large population database, indicating this variant is rare. It has been interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/56098/). Taken together, this variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Nov 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001155610.23
First in ClinVar: Feb 03, 2020 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Non-ketotic hyperglycinemia
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000081942.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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Pathogenic
(Jul 26, 2021)
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no assertion criteria provided
Method: clinical testing
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Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075809.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. | Coughlin CR 2nd | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27362913 |
Three-dimensional evaluation of different prosthesis retention systems using finite element analysis and the Von Mises stress test. | Lauritano F | Minerva stomatologica | 2016 | PMID: 27362813 |
Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. | Swanson MA | Annals of neurology | 2015 | PMID: 26179960 |
Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation. | Korman SH | Annals of neurology | 2006 | PMID: 16404748 |
Text-mined citations for rs386833580 ...
HelpRecord last updated Jun 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.