ClinVar Genomic variation as it relates to human health
NM_000481.4(AMT):c.471+2T>C
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.471+2T>C
Variation ID: 56233 Accession: VCV000056233.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 49420209 (GRCh38) [ NCBI UCSC ] 3: 49457642 (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 Feb 20, 2024 Sep 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000481.4:c.471+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001164710.2:c.340-421T>C intron variant NM_001164711.2:c.303+2T>C splice donor NM_001164712.2:c.471+2T>C splice donor NC_000003.12:g.49420209A>G NC_000003.11:g.49457642A>G NG_015986.1:g.7470T>C LRG_537:g.7470T>C LRG_537t1:c.471+2T>C - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:49420208:A:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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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AMT | - | - |
GRCh38 GRCh37 |
628 | 719 |
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 (7) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2023 | RCV000049645.19 |
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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Pathogenic
(Feb 07, 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: SCV002103503.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: AMT c.471+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: AMT c.471+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251476 control chromosomes (gnomAD). c.471+2T>C has been reported in the literature in multiple compound heterozygous individuals affected with Glycine Encephalopathy (aka. Non-Ketotic Hyperglycinemia) (Kure_2006, Swanson_2015, Coughlin_2017). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 02, 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: SCV004196852.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 26, 2020)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001451514.1
First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020 |
Comment:
The AMT c.471+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant … (more)
The AMT c.471+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in a compound heterozygous state in at least two unrelated families affected with the neonatal form of glycine encephalopathy (also known as nonketotic hyperglycinemia; NKH). The c.471+2T>C variant was found in trans with a missense variant in one family and with a frameshift variant in the second family (Kure et al. 2006). The c.471+2T>C variant was also identified in five individuals from a cohort of 578 families suspected to have classic NKH (Coughlin et al. 2016). Control data are unavailable for this variant which is found at a frequency of 0.000029 in the Latino population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the potential impact of slice donor variants, the variant's rarity and application of the ACMG criteria, the c.471+2T>C variant is classified as pathogenic for glycine encephalopathy. (less)
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Pathogenic
(Sep 28, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000636426.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 56233). This sequence change affects a donor splice site in intron 4 of the AMT gene. … (more)
ClinVar contains an entry for this variant (Variation ID: 56233). This sequence change affects a donor splice site in intron 4 of the AMT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403). This variant is present in population databases (rs386833684, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with nonketotic hyperglycinemia (PMID: 16450403). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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:
unknown
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082052.1
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
(Jan 10, 2018)
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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: SCV000797065.2
First in ClinVar: May 30, 2018 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 2020)
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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: SCV001460427.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Correction: The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. | Coughlin CR | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29300369 |
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 |
Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. | Kure S | Human mutation | 2006 | PMID: 16450403 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs386833684 ...
HelpRecord last updated Sep 29, 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.