ClinVar Genomic variation as it relates to human health
NM_000481.4(AMT):c.887G>A (p.Arg296His)
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_000481.4(AMT):c.887G>A (p.Arg296His)
Variation ID: 56239 Accession: VCV000056239.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 49417964 (GRCh38) [ NCBI UCSC ] 3: 49455397 (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 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000481.4:c.887G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000472.2:p.Arg296His missense NM_001164710.2:c.755G>A NP_001158182.1:p.Arg252His missense NM_001164711.2:c.719G>A NP_001158183.1:p.Arg240His missense NM_001164712.2:c.887G>A NP_001158184.1:p.Arg296His missense NR_028435.2:n.896G>A non-coding transcript variant NC_000003.12:g.49417964C>T NC_000003.11:g.49455397C>T NG_015986.1:g.9715G>A LRG_537:g.9715G>A LRG_537t1:c.887G>A LRG_537p1:p.Arg296His - Protein change
- R240H, R252H, R296H
- Other names
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- Canonical SPDI
- NC_000003.12:49417963:C:T
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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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
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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AMT | - | - |
GRCh38 GRCh37 |
622 | 711 |
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
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
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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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2023 | RCV000049651.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000436156.6 |
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
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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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Glycine encephalopathy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Suma Genomics
Accession: SCV001837616.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
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Likely pathogenic
(Sep 27, 2023)
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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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GeneDx
Accession: SCV000512023.4
First in ClinVar: Mar 08, 2017 Last updated: Oct 05, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26179960, 34630504, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26179960, 34630504, 16051266, 16450403, 12948742, 27362913) (less)
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Pathogenic
(Jun 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycine encephalopathy 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004196314.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 23, 2021)
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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: SCV000813475.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Arg296 amino acid residue in AMT. Other variant(s) that disrupt this residue have been observed in individuals with AMT-related conditions (PMID: … (more)
This variant disrupts the p.Arg296 amino acid residue in AMT. Other variant(s) that disrupt this residue have been observed in individuals with AMT-related conditions (PMID: 12948742, 16450403, 26179960, 27362913, 28244183), which suggests that this may be a clinically significant amino acid residue. 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 AMT protein function. ClinVar contains an entry for this variant (Variation ID: 56239). This missense change has been observed in individual(s) with glycine encephalopathy or non-ketotic hyperglycinemia (PMID: 12948742, 16450403, 26179960, 27362913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs386833690, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 296 of the AMT protein (p.Arg296His). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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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: SCV004699977.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
AMT: PM3:Very Strong, PM2
Number of individuals with the variant: 1
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Likely pathogenic
(May 21, 2022)
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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: SCV002548045.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: AMT c.887G>A (p.Arg296His) 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: AMT c.887G>A (p.Arg296His) 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 allele was found at a frequency of 3.3e-05 in 242288 control chromosomes. c.887G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Toone_2003, Coughlin_2017, Swanson_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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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: SCV000082058.1
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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Likely pathogenic
(Jun 02, 2017)
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no assertion criteria provided
Method: clinical testing
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Glycine encephalopathy 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800767.2
First in ClinVar: Jul 24, 2013 Last updated: Dec 23, 2019 |
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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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Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease. | Bravo-Alonso I | Human mutation | 2017 | PMID: 28244183 |
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 |
Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. | Swanson MA | Annals of neurology | 2015 | PMID: 26179960 |
Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. | Kure S | Human mutation | 2006 | PMID: 16450403 |
Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia. | Okamura-Ikeda K | Journal of molecular biology | 2005 | PMID: 16051266 |
Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH). | Toone JR | Molecular genetics and metabolism | 2003 | PMID: 12948742 |
Text-mined citations for rs386833690 ...
HelpRecord last updated Apr 15, 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.