This sequence change creates a premature translational stop signal (p.Ser6Lysfs*22) in the AMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403). This variant is present in population databases (rs773988915, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of glycine encephalopathy (PMID: 27362913, 30105116). This variant is also known as c.14_15insT. ClinVar contains an entry for this variant (Variation ID: 594847). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000481.4(AMT):c.14dup (p.Ser6fs)
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.
(6)
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/Likely pathogenic
6
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.14dup (p.Ser6fs)
Variation ID: 594847 Accession: VCV000594847.18
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 3p21.31 3: 49422436-49422437 (GRCh38) [ NCBI UCSC ] 3: 49459869-49459870 (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 Dec 16, 2018 Oct 20, 2024 Jan 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000481.4:c.14dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000472.2:p.Ser6fs frameshift NM_032316.3:c.*2396dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_000481.3:c.14dupT frameshift NM_001164710.2:c.14dup NP_001158182.1:p.Ser6fs frameshift NM_001164711.2:c.14dup NP_001158183.1:p.Ser6fs frameshift NM_001164712.2:c.14dup NP_001158184.1:p.Ser6fs frameshift NR_028435.2:n.37dup non-coding transcript variant NC_000003.12:g.49422437dup NC_000003.11:g.49459870dup NG_015986.1:g.5242dup NG_033046.1:g.11888dup NG_099408.1:g.437dup LRG_537:g.5242dup LRG_537t1:c.14dup LRG_537p1:p.Ser6Lysfs - Protein change
- S6fs
- Other names
- -
- Canonical SPDI
- NC_000003.12:49422436:A:AA
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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) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 | |
| NICN1 | - | - |
GRCh38 GRCh37 |
6 | 99 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000730238.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 29, 2023 | RCV001868952.7 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 6, 2021 | RCV004576965.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000857963.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: mixed
|
|
|
Pathogenic
(May 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004196325.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Nov 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Non-ketotic hyperglycinemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002245876.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser6Lysfs*22) in the AMT gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ser6Lysfs*22) in the AMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403). This variant is present in population databases (rs773988915, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of glycine encephalopathy (PMID: 27362913, 30105116). This variant is also known as c.14_15insT. ClinVar contains an entry for this variant (Variation ID: 594847). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005060970.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Comment:
The frameshift c.14dup (p.Ser6LysfsTer22) variant in AMT gene has been reported in individuals affected with AMT-related disorders (Coughlin et al., 2017; Radha Rama Devi et … (more)
The frameshift c.14dup (p.Ser6LysfsTer22) variant in AMT gene has been reported in individuals affected with AMT-related disorders (Coughlin et al., 2017; Radha Rama Devi et al., 2018). The p.Ser6LysfsTer22 variant is has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant is also known as c.14_15insT. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 6, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Ser6LysfsTer22. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in AMT are known to be pathogenic (Kure et al., 2006). However, functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another significant variant in AMT gene, the molecular diagnosis is not confirmed. (less)
|
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycine encephalopathy 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV003921822.2
First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycine encephalopathy (MIM#605899). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (10 heterozygotes, 0 homozygotes). (SP) 0701 – Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other NMD predicted variants have been reported as pathogenic in ClinVar. (SP) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and in a patient with classic nonketotic hyperglycinemia (PMID: 27362913). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004703313.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
AMT: PVS1, PM2, PM3
Number of individuals with the variant: 3
|
Comment:
Comment:
The frameshift c.14dup (p.Ser6LysfsTer22) variant in AMT gene has been reported in individuals affected with AMT-related disorders (Coughlin et al., 2017; Radha Rama Devi et al., 2018). The p.Ser6LysfsTer22 variant is has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant is also known as c.14_15insT. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 6, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Ser6LysfsTer22. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in AMT are known to be pathogenic (Kure et al., 2006). However, functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another significant variant in AMT gene, the molecular diagnosis is not confirmed.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycine encephalopathy (MIM#605899). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (10 heterozygotes, 0 homozygotes). (SP) 0701 – Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other NMD predicted variants have been reported as pathogenic in ClinVar. (SP) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and in a patient with classic nonketotic hyperglycinemia (PMID: 27362913). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
AMT: PVS1, PM2, PM3
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:
This sequence change creates a premature translational stop signal (p.Ser6Lysfs*22) in the AMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403). This variant is present in population databases (rs773988915, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of glycine encephalopathy (PMID: 27362913, 30105116). This variant is also known as c.14_15insT. ClinVar contains an entry for this variant (Variation ID: 594847). For these reasons, this variant has been classified as Pathogenic.
Comment:
The frameshift c.14dup (p.Ser6LysfsTer22) variant in AMT gene has been reported in individuals affected with AMT-related disorders (Coughlin et al., 2017; Radha Rama Devi et al., 2018). The p.Ser6LysfsTer22 variant is has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant is also known as c.14_15insT. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 6, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Ser6LysfsTer22. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in AMT are known to be pathogenic (Kure et al., 2006). However, functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another significant variant in AMT gene, the molecular diagnosis is not confirmed.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycine encephalopathy (MIM#605899). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (10 heterozygotes, 0 homozygotes). (SP) 0701 – Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other NMD predicted variants have been reported as pathogenic in ClinVar. (SP) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and in a patient with classic nonketotic hyperglycinemia (PMID: 27362913). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
AMT: PVS1, PM2, PM3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of Two Novel Mutations in Aminomethyltransferase Gene in Cases of Glycine Encephalopathy. | Radha Rama Devi A | Journal of pediatric genetics | 2018 | PMID: 30105116 |
| 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 |
| Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. | Kure S | Human mutation | 2006 | PMID: 16450403 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AMT | - | - | - | - |
Text-mined citations for rs773988915 ...
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.