Variant summary: The AMT c.959G>A (p.Arg320His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control population database ExAC at a frequency of 0.0000745 (9/120770 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic AMT variant (0.0014049). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Several publications show the variant segregating with disease (e.g., Toone_MGM_2000) and additional studies provide functional data suggesting that the variant is disease causing (e.g., Swanson_Ann Neurol_2015). Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000481.4(AMT):c.959G>A (p.Arg320His)
Germline
Classification
Help
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.
(16)
Help
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
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000481.4(AMT):c.959G>A (p.Arg320His)
Variation ID: 11979 Accession: VCV000011979.51
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p21.31 3: 49417892 (GRCh38) [ NCBI UCSC ] 3: 49455325 (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 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000481.4:c.959G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000472.2:p.Arg320His missense NM_001164710.2:c.827G>A NP_001158182.1:p.Arg276His missense NM_001164711.2:c.791G>A NP_001158183.1:p.Arg264His missense NM_001164712.2:c.959G>A NP_001158184.1:p.Arg320His missense NR_028435.2:n.968G>A non-coding transcript variant NC_000003.12:g.49417892C>T NC_000003.11:g.49455325C>T NG_015986.1:g.9787G>A LRG_537:g.9787G>A LRG_537t1:c.959G>A LRG_537p1:p.Arg320His P48728:p.Arg320His - Protein change
- R320H, R264H, R276H
- Other names
- -
- Canonical SPDI
- NC_000003.12:49417891:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| AMT | - | - |
GRCh38 GRCh37 |
629 | 720 | |
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. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 9, 2024 | RCV000012759.48 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2024 | RCV001090581.28 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV003230357.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2024 | RCV004566727.1 |
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
(Feb 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811064.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Glycine encephalopathy 2
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051921.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696806.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The AMT c.959G>A (p.Arg320His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a … (more)
Variant summary: The AMT c.959G>A (p.Arg320His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control population database ExAC at a frequency of 0.0000745 (9/120770 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic AMT variant (0.0014049). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Several publications show the variant segregating with disease (e.g., Toone_MGM_2000) and additional studies provide functional data suggesting that the variant is disease causing (e.g., Swanson_Ann Neurol_2015). Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 1
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059877.1
First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022 |
|
|
|
Pathogenic
(Sep 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 2
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023202.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000636431.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 320 of the AMT protein (p.Arg320His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 320 of the AMT protein (p.Arg320His). This variant is present in population databases (rs121964985, gnomAD 0.02%). This missense change has been observed in individual(s) with glycine encephalopathy with plasma and CSF Glycine levels diagnostic for this condition, as homozygous (PMID: 8005589, 10873393, 12948742). ClinVar contains an entry for this variant (Variation ID: 11979). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AMT function (PMID: 23352163). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004196190.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Feb 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005202080.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate a damaging effect with loss of enzyme activity and significant reduction of glycine cleavage activity (PMID: 23352163); In silico analysis, which … (more)
Published functional studies demonstrate a damaging effect with loss of enzyme activity and significant reduction of glycine cleavage activity (PMID: 23352163); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8005589, 10873393, 12948742, 27362913, 31589614, 23352163) (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246195.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
AMT: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001456310.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954361.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Apr 01, 2001)
|
no assertion criteria provided
Method: literature only
|
GLYCINE ENCEPHALOPATHY 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032994.5
First in ClinVar: Apr 04, 2013 Last updated: Jun 03, 2023 |
Comment on evidence:
For discussion of the arg320-to-his (R320H) mutation in the AMT gene that was found in compound heterozygous state in patients with glycine encephalopathy (GCE2; 620398) … (more)
For discussion of the arg320-to-his (R320H) mutation in the AMT gene that was found in compound heterozygous state in patients with glycine encephalopathy (GCE2; 620398) by Nanao et al. (1994), see 238310.0002. In a patient with glycine encephalopathy, Toone et al. (2000) identified homozygosity for the R320H mutation in the AMT gene. Toone et al. (2001) screened a DNA bank from 50 patients with enzymatically confirmed nonketotic hyperglycinemia and identified the R320H mutation in 7% of alleles. (less)
|
|
|
Likely pathogenic
(Nov 18, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Glycine encephalopathy 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132332.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800001.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928267.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Non-ketotic hyperglycinemia
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000086790.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
|
|
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Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 320 of the AMT protein (p.Arg320His). This variant is present in population databases (rs121964985, gnomAD 0.02%). This missense change has been observed in individual(s) with glycine encephalopathy with plasma and CSF Glycine levels diagnostic for this condition, as homozygous (PMID: 8005589, 10873393, 12948742). ClinVar contains an entry for this variant (Variation ID: 11979). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AMT function (PMID: 23352163). For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate a damaging effect with loss of enzyme activity and significant reduction of glycine cleavage activity (PMID: 23352163); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8005589, 10873393, 12948742, 27362913, 31589614, 23352163)
Comment:
AMT: PM3:Very Strong, PM2, PS3:Supporting
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:
Variant summary: The AMT c.959G>A (p.Arg320His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control population database ExAC at a frequency of 0.0000745 (9/120770 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic AMT variant (0.0014049). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Several publications show the variant segregating with disease (e.g., Toone_MGM_2000) and additional studies provide functional data suggesting that the variant is disease causing (e.g., Swanson_Ann Neurol_2015). Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 320 of the AMT protein (p.Arg320His). This variant is present in population databases (rs121964985, gnomAD 0.02%). This missense change has been observed in individual(s) with glycine encephalopathy with plasma and CSF Glycine levels diagnostic for this condition, as homozygous (PMID: 8005589, 10873393, 12948742). ClinVar contains an entry for this variant (Variation ID: 11979). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AMT function (PMID: 23352163). For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate a damaging effect with loss of enzyme activity and significant reduction of glycine cleavage activity (PMID: 23352163); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8005589, 10873393, 12948742, 27362913, 31589614, 23352163)
Comment:
AMT: PM3:Very Strong, PM2, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Nonketotic Hyperglycinemia. | Adam MP | - | 2019 | PMID: 20301531 |
| 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 |
| Nonketotic hyperglycinemia: novel mutation in the aminomethyl transferase gene. Case report. | Gencpinar P | Archivos argentinos de pediatria | 2016 | PMID: 27164344 |
| Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. | Swanson MA | Annals of neurology | 2015 | PMID: 26179960 |
| Using whole-exome sequencing to identify inherited causes of autism. | Yu TW | Neuron | 2013 | PMID: 23352163 |
| Ketogenic diet in early myoclonic encephalopathy due to non ketotic hyperglycinemia. | Cusmai R | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2012 | PMID: 22261077 |
| 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 |
| Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): a strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH). | Toone JR | Molecular genetics and metabolism | 2001 | PMID: 11286506 |
| Identification of the first reported splice site mutation (IVS7-1G-->A) in the aminomethyltransferase (T-protein) gene (AMT) of the glycine cleavage complex in 3 unrelated families with nonketotic hyperglycinemia. | Toone JR | Human mutation | 2001 | PMID: 11139253 |
| Biochemical and molecular investigations of patients with nonketotic hyperglycinemia. | Toone JR | Molecular genetics and metabolism | 2000 | PMID: 10873393 |
| Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia. | Nanao K | Human genetics | 1994 | PMID: 8005589 |
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Text-mined citations for rs121964985 ...
HelpThese 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
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.