NM_004539.4(NARS1):c.1600C>T (p.Arg534Ter) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 23, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002537635.2

Allele description [Variation Report for NM_004539.4(NARS1):c.1600C>T (p.Arg534Ter)]

NM_004539.4(NARS1):c.1600C>T (p.Arg534Ter)

Gene:

NARS1:asparaginyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q21.31

Genomic location:

Preferred name:

NM_004539.4(NARS1):c.1600C>T (p.Arg534Ter)

HGVS:

NC_000018.10:g.57601699G>A
NM_004539.4:c.1600C>TMANE SELECT
NP_004530.1:p.Arg534Ter
NC_000018.9:g.55268931G>A
NM_004539.3:c.1600C>T

Protein change:

R534*; ARG534TER

Links:

OMIM: 108410.0006; dbSNP: rs2051507892

NCBI 1000 Genomes Browser:

rs2051507892

Molecular consequence:

NM_004539.4:c.1600C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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SRA Links for BioSample (Select 6677995) (1)
SRA
melanoma-associated antigen D2 [Homo sapiens]
melanoma-associated antigen D2 [Homo sapiens]
gi|19387846|ref|NP_055414.2|

Protein
predicted protein [Nematostella vectensis]
predicted protein [Nematostella vectensis]
gi|156220590|gb|EDO41456.1||gnl|WGS |NEMVEDRAFT_v1g206625

Protein
BioSample links for Nucleotide (Select 7248268) (1)
BioSample
BioSample entry for Human chromosome 14
BioSample entry for Human chromosome 14

biosample

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002961448	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 23, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32738225, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002961448

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 23, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Efthymiou S, O'Connor E, Mendes MI, Jennings M, Maroofian R, Davagnanam I, Mankad K, Lopez MR, Salpietro V, Harripaul R, Badalato L, Walia J, Francklyn CS, Athanasiou-Fragkouli A, Sullivan R, Desai S, Baranano K, Zafar F, Rana N, Ilyas M, Horga A, et al.

Am J Hum Genet. 2020 Aug 6;107(2):311-324. doi: 10.1016/j.ajhg.2020.06.016. Epub 2020 Jul 31.

PubMed [citation]

PMID:: 32738225
PMCID:: PMC7413890

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002961448.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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