NM_004184.4(WARS1):c.997G>A (p.Ala333Thr) AND Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities

Germline classification:: Uncertain significance (2 submissions)
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:: RCV003223371.2

Allele description [Variation Report for NM_004184.4(WARS1):c.997G>A (p.Ala333Thr)]

NM_004184.4(WARS1):c.997G>A (p.Ala333Thr)

Gene:

WARS1:tryptophanyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.2

Genomic location:

Preferred name:

NM_004184.4(WARS1):c.997G>A (p.Ala333Thr)

Other names:

A333T

HGVS:

NC_000014.9:g.100342514C>T
NG_029914.1:g.38830G>A
NM_004184.4:c.997G>AMANE SELECT
NM_173701.2:c.997G>A
NM_213645.2:c.874G>A
NM_213646.2:c.874G>A
NP_004175.2:p.Ala333Thr
NP_776049.1:p.Ala333Thr
NP_998810.1:p.Ala292Thr
NP_998811.1:p.Ala292Thr
NC_000014.8:g.100808851C>T

Protein change:

A292T; ALA333THR

Links:

OMIM: 191050.0005

Molecular consequence:

NM_004184.4:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173701.2:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_213645.2:c.874G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_213646.2:c.874G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities (NEDMSBA)
Identifiers:: MONDO: MONDO:0957218; MedGen: C5830413; OMIM: 620317

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003918832	OMIM	no assertion criteria provided	Pathogenic (Apr 19, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004034970	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	unknown	curation	PubMed (3) [See all records that cite these PMIDs] 35815345, 34585293, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003918832

OMIM

no assertion criteria provided

Pathogenic
(Apr 19, 2023)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004034970

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

unknown

curation

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function.

Lin SJ, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon ML, Rüschendorf F, Kong IK, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, et al.

Hum Mutat. 2022 Oct;43(10):1472-1489. doi: 10.1002/humu.24435. Epub 2022 Jul 21.

PubMed [citation]

PMID:: 35815345

Four pedigrees with aminoacyl-tRNA synthetase abnormalities.

Okamoto N, Miya F, Tsunoda T, Kanemura Y, Saitoh S, Kato M, Yanagi K, Kaname T, Kosaki K.

Neurol Sci. 2022 Apr;43(4):2765-2774. doi: 10.1007/s10072-021-05626-z. Epub 2021 Sep 28.

PubMed [citation]

PMID:: 34585293

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV003918832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the c.997G-A transition (c.997G-A, NM_004184) in the WARS1 gene, resulting in an ala333-to-thr (A333T) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with microcephaly, speech delay, and brain abnormalities (NEDMSBA; 620317) by Okamoto et al. (2022), see 191050.0004.

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

From SIB Swiss Institute of Bioinformatics, SCV004034970.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

This variant is interpreted as variant of uncertain significance for Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, autosomal recessive. 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); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3).

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

Last Updated: Dec 2, 2023

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