ClinVar Genomic variation as it relates to human health
NM_001673.5(ASNS):c.146G>A (p.Arg49Gln)
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
-
NM_001673.5(ASNS):c.146G>A (p.Arg49Gln)
Variation ID: 383733 Accession: VCV000383733.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q21.3 7: 97869011 (GRCh38) [ NCBI UCSC ] 7: 97498323 (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 Mar 8, 2017 Mar 10, 2024 Dec 30, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001673.5:c.146G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001664.3:p.Arg49Gln missense NM_001178075.2:c.83G>A NP_001171546.1:p.Arg28Gln missense NM_001178076.2:c.-1+3340G>A intron variant NM_001178077.1:c.-1+3030G>A intron variant NM_001352496.2:c.146G>A NP_001339425.1:p.Arg49Gln missense NM_133436.3:c.146G>A NP_597680.2:p.Arg49Gln missense NM_183356.4:c.146G>A NP_899199.2:p.Arg49Gln missense NR_147989.1:n.1775G>A non-coding transcript variant NC_000007.14:g.97869011C>T NC_000007.13:g.97498323C>T NG_033870.2:g.64552G>A - Protein change
- R49Q, R28Q
- Other names
- -
- Canonical SPDI
- NC_000007.14:97869010: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), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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. |
|||
ASNS | - | - |
GRCh38 GRCh37 |
5 | 730 | |
CZ1P-ASNS | - | - | - | GRCh38 | - | 712 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 7, 2023 | RCV000432896.6 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 30, 2023 | RCV000714524.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002274029.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Feb 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000524216.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The R49Q variant in the ASNS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The R49Q variant in the ASNS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R49Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R49Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R49Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
|
|
Likely pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Asparagine synthetase deficiency
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845219.2
First in ClinVar: Nov 03, 2018 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 3
Sex: mixed
Geographic origin: Iran
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV001468998.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental delay
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002558923.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
Pathogenic
(Oct 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001587973.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 49 of the ASNS protein (p.Arg49Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 49 of the ASNS protein (p.Arg49Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with asparagine synthetase deficiency (PMID: 29279279, 30978478, 33287870). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 383733). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASNS protein function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Dec 30, 2023)
|
criteria provided, single submitter
Method: curation
|
Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891623.2
First in ClinVar: Nov 03, 2018 Last updated: Mar 10, 2024 |
Geographic origin: Middle East
|
|
Pathogenic
(May 26, 2020)
|
no assertion criteria provided
Method: literature only
|
ASPARAGINE SYNTHETASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001446397.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Comment on evidence:
In 2 sibs, born to consanguineous Emirati parents, with asparagine synthetase deficiency (ASNSD; 615574), Sacharow et al. (2018) identified a homozygous c.146G-A transition (c.146G-A, NM_183356) … (more)
In 2 sibs, born to consanguineous Emirati parents, with asparagine synthetase deficiency (ASNSD; 615574), Sacharow et al. (2018) identified a homozygous c.146G-A transition (c.146G-A, NM_183356) in the ASNS gene, resulting in an arg49-to-gln (R49Q) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant has a low frequency (7.21 x 10(-6)) in the gnomAD database. Structural modeling suggested that the mutation affects the glutamine binding pocket of the protein. Studies in fibroblasts from patients showed that little to no cellular growth compared to controls in asparagine-depleted cell media, and fibroblasts from heterozygous parents showed moderate cellular growth compared to controls. The R49G variant did not appear to affect ASNS synthesis or stability. (less)
|
|
Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Asparagine synthetase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453755.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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 |
---|---|---|---|---|
Pathogenic variants identified by whole-exome sequencing in 43 patients with epilepsy. | Zhang L | Human genomics | 2020 | PMID: 33287870 |
Molecular diagnosis of asparagine synthetase (ASNS) deficiency in two Indian families and literature review of 29 ASNS deficient cases. | Radha Rama Devi A | Gene | 2019 | PMID: 30978478 |
Characterization of a novel variant in siblings with Asparagine Synthetase Deficiency. | Sacharow SJ | Molecular genetics and metabolism | 2018 | PMID: 29279279 |
Text-mined citations for rs769236847 ...
HelpRecord last updated Mar 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.