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NM_015836.4(WARS2):c.37T>G (p.Trp13Gly) AND WARS2-related disorder

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
May 3, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV003235260.4

Allele description [Variation Report for NM_015836.4(WARS2):c.37T>G (p.Trp13Gly)]

NM_015836.4(WARS2):c.37T>G (p.Trp13Gly)

Genes:
LOC129931299:ATAC-STARR-seq lymphoblastoid active region 1590 [Gene]
WARS2-AS1:WARS2 antisense RNA 1 [Gene - HGNC]
WARS2:tryptophanyl tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p12
Genomic location:
Preferred name:
NM_015836.4(WARS2):c.37T>G (p.Trp13Gly)
Other names:
p.W13G
HGVS:
  • NC_000001.11:g.119140608A>C
  • NG_050658.1:g.5181T>G
  • NM_001378226.1:c.-118T>G
  • NM_001378227.1:c.-309T>G
  • NM_001378228.1:c.37T>G
  • NM_001378229.1:c.37T>G
  • NM_001378230.1:c.-437T>G
  • NM_001378231.1:c.37T>G
  • NM_015836.4:c.37T>GMANE SELECT
  • NM_201263.2:c.37T>G
  • NP_001365157.1:p.Trp13Gly
  • NP_001365158.1:p.Trp13Gly
  • NP_001365160.1:p.Trp13Gly
  • NP_056651.1:p.Trp13Gly
  • NP_056651.1:p.Trp13Gly
  • NP_957715.1:p.Trp13Gly
  • NC_000001.10:g.119683231A>C
  • NC_000001.10:g.119683231A>C
  • NM_015836.3(WARS2):c.37T>G
  • NM_015836.3:c.37T>G
  • NM_015836.4:c.37T>G
  • NR_125974.1:n.213A>C
  • NR_125975.1:n.213A>C
  • NR_125976.1:n.213A>C
  • NR_125977.1:n.213A>C
  • p.Trp13Gly
Protein change:
W13G; TRP13GLY
Links:
OMIM: 604733.0002; dbSNP: rs139548132
NCBI 1000 Genomes Browser:
rs139548132
Molecular consequence:
  • NM_001378226.1:c.-118T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001378227.1:c.-309T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001378230.1:c.-437T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001378228.1:c.37T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378229.1:c.37T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378231.1:c.37T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015836.4:c.37T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201263.2:c.37T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_125974.1:n.213A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_125975.1:n.213A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_125976.1:n.213A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_125977.1:n.213A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
WARS2-related disorder
Synonyms:
WARS2-Related Disorders; WARS2 related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003933944Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(May 3, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV004109532PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Feb 24, 2023) 		germlineclinical testing

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

SCV005368725Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN
no assertion criteria provided
Pathogenic
(Jan 4, 2023) 		paternalclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedpaternalyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Targeted next generation sequencing identifies novel pathogenic variants and provides molecular diagnoses in a cohort of pediatric and adult patients with unexplained mitochondrial dysfunction.

Nogueira C, Silva L, Pereira C, Vieira L, Leão Teles E, Rodrigues E, Campos T, Janeiro P, Gaspar A, Dupont J, Bandeira A, Martins E, Magalhães M, Sequeira S, Vieira JP, Santos H, Vilarinho S, Vilarinho L.

Mitochondrion. 2019 Jul;47:309-317. doi: 10.1016/j.mito.2019.02.006. Epub 2019 Mar 1.

PubMed [citation]
PMID:
30831263

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Brunet T, Jech R, Brugger M, Kovacs R, Alhaddad B, Leszinski G, Riedhammer KM, Westphal DS, Mahle I, Mayerhanser K, Skorvanek M, Weber S, Graf E, Berutti R, Necpál J, Havránková P, Pavelekova P, Hempel M, Kotzaeridou U, Hoffmann GF, Leiz S, Makowski C, et al.

Clin Genet. 2021 Jul;100(1):14-28. doi: 10.1111/cge.13946. Epub 2021 Mar 1.

PubMed [citation]
PMID:
33619735
See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003933944.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: WARS2 c.37T>G (p.Trp13Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 250992 control chromosomes in the gnomAD database, including 6 homozygotes. c.37T>G has been reported in the literature in numerous compound heterozygous individuals affected with WARS2-Related Disorders, including several patients with infantile-onset Parkinsonism (e.g., Musante_2017, Burke_2018, Nogueira_2019, Hubers_2019, Martinelli_2002, Brunet_2021, Skorvanek_2022); pathogenic variants have been confirmed in trans in the majority of these individuals and the variant has been shown to segregate with disease in related individuals. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in impaired mitochondrial localizaiton in vitro (e.g., Musante_2017), and in compound heterozygous patient fibroblasts, results in reduced WARS2 protein levels and impairs mitochondrial respiratory chain activity (e.g., Burke_2018, Martinelli_2020, Skorvanek_2022). The following publications have been ascertained in the context of this evaluation (PMID: 33619735, 29120065, 31970218, 32120303, 28236339, 30831263, 34890876). Multiple ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: pathogenic (n = 4), likely pathogenic (n = 2), VUS (n = 4), and likely benign (n = 2). The presence of homozygotes in the gnomAD control population as well as the many patients found to harbor this variant and functional evidence combine to suggest this variant represents a hypomorphic allele. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From PreventionGenetics, part of Exact Sciences, SCV004109532.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The WARS2 c.37T>G variant is predicted to result in the amino acid substitution p.Trp13Gly. The c.37T>G (p.Trp13Gly) variant has been described as a hypomorphic allele and reported in the compound heterozygous state in multiple unrelated families affected with intellectual disability or infantile onset leukoencephalopathy (Musante et al. 2017. PubMed ID: 28236339 ; Burke et al. 2018. PubMed ID: 29120065; Nogueira et al. 2019. PubMed ID: 30831263; Martinelli et al. 2020. PubMed ID: 32120303; Hubers et al. 2020. PubMed ID: 31970218; Skorvanek et al. 2022. PubMed ID: 34890876). In vitro study showed this variant may affect the mitochondrial localization signal (Musante et al. 2017. PubMed ID: 28236339). This variant is reported in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 6 homozygous individuals of unknown phenotype (http://gnomad.broadinstitute.org/variant/1-119683231-A-C), and is only expected to cause disease when found in trans (on the opposite chromosome) with a second more deleterious variant in this gene (Skorvanek et al. 2022. PubMed ID: 34890876). Based on the collective evidence, we interpret this variant to be a likely pathogenic variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV005368725.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providedBloodnot provided1not providednot providednot provided

Last Updated: Nov 3, 2024