ClinVar Genomic variation as it relates to human health
NM_004539.4(NARS1):c.1600C>T (p.Arg534Ter)
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_004539.4(NARS1):c.1600C>T (p.Arg534Ter)
Variation ID: 982711 Accession: VCV000982711.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.31 18: 57601699 (GRCh38) [ NCBI UCSC ] 18: 55268931 (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 Oct 31, 2020 Apr 20, 2024 Aug 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004539.4:c.1600C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004530.1:p.Arg534Ter nonsense NC_000018.10:g.57601699G>A NC_000018.9:g.55268931G>A - Protein change
- R534*
- Other names
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- Canonical SPDI
- NC_000018.10:57601698:G:A
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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.
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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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NARS1 | - | - |
GRCh38 GRCh37 |
121 | 192 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV001262349.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002274170.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 15, 2022 | RCV003127739.1 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 7, 2022 | RCV001267639.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 23, 2022 | RCV002537635.2 |
Submissions - Germline
Classification
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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
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440176.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(May 10, 2021)
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criteria provided, single submitter
Method: curation
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Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV001593254.1
First in ClinVar: May 14, 2021 Last updated: May 14, 2021 |
Comment:
This variant is interpreted as pathogenic for Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant. The following ACMG Tag(s) were applied: … (more)
This variant is interpreted as pathogenic for Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Assumed de novo, but no confirmation of paternity and maternity (PM6 upgraded to very strong); Well-established functional studies show a deleterious effect (PS3 dowgraded to moderate). (less)
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002012096.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). This variant has been reported as de novoo in smiliarly affected inidividuals (PMID:32738225, PS2 and PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32738225, PS3). herefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Constipation (present) , Abnormal facial shape (present) , Failure to thrive (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , … (more)
Constipation (present) , Abnormal facial shape (present) , Failure to thrive (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Growth delay (present) , Intellectual disability (present) , Microcephaly (present) , Protruding ear (present) , Thick upper lip vermilion (present) , Seizure (present) , Short philtrum (present) , Mild short stature (present) , Delayed speech and language development (present) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities
Affected status: yes
Allele origin:
de novo
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559224.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
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Pathogenic
(Nov 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Variantyx, Inc.
Accession: SCV002754535.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
This is a nonsense variant in the NARS1 gene (OMIM 108410). Heterozygous pathogenic variants in this gene have been associated with autosomal dominant neurodevelopmental disorder … (more)
This is a nonsense variant in the NARS1 gene (OMIM 108410). Heterozygous pathogenic variants in this gene have been associated with autosomal dominant neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG). This variant was identified de novo in this individual (PS2_Moderate). This variant has been reported as de novo in the heterozygous state in multiple unrelated affected individuals (PMID: 32738225) (PS4). In vitro and in vivo functional studies have shown that this variant results in a truncated protein (lacking the last 14 amino acids) with a gain-of-function effect (PMID: 32738225) (PS3; PM4). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2_Supporting). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant NEDMILEG. (less)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental disorder
Affected status: yes
Allele origin:
de novo
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV003803863.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Sex: female
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Pathogenic
(Apr 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002961448.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence … (more)
Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence change creates a premature translational stop signal (p.Arg534*) in the NARS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the NARS protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with NARS1-related neurodevelopmental delay (PMID: 32738225). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 982711). Experimental studies have shown that this premature translational stop signal affects NARS function (PMID: 32738225). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847309.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg534X (c.1600C>T) variant in NARS1 has been reported de novo in 6 unrelated individuals with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait … (more)
The p.Arg534X (c.1600C>T) variant in NARS1 has been reported de novo in 6 unrelated individuals with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (Manole 2020 PMID: 32738225). The alteration was absent from large population studies. This variant has been reported in ClinVar (Variation ID 982711) by multiple submitters. This nonsense variant leads to a premature termination codon at position 534. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. The truncation is predicted to disrupt the catalytic domain of NARS1 (Manole 2020 PMID: 32738225). In vitro functional studies demonstrate decreased enzymatic activity in proband-derived cells, and a zebrafish model of the variant exhibits a dominant negative effect causing cyclopia and gastrulation defects (Manole 2020 PMID: 32738225). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities. ACMG/AMP Criteria applied: PM6_Strong, PS4, PM4, PM1, PM2_Supporting, PS3_Supporting. (less)
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Pathogenic
(Nov 18, 2020)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, EPILEPSY, AND GAIT ABNORMALITIES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001445823.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment on evidence:
In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; 619092), Manole et al. (2020) identified a … (more)
In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; 619092), Manole et al. (2020) identified a de novo heterozygous c.1600C-T transition (c.1600C-T, NM_004539.4) in the NARS1 gene, resulting in an arg534-to-ter (R534X) substitution in the C terminus at a conserved residue 15 amino acids from the end of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect. (less)
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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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De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects. | Manole A | American journal of human genetics | 2020 | PMID: 32738225 |
Text-mined citations for rs2051507892 ...
HelpRecord last updated May 01, 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.