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NM_015836.4(WARS2):c.791A>G (p.Tyr264Cys) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Jun 26, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000209945.9

Allele description [Variation Report for NM_015836.4(WARS2):c.791A>G (p.Tyr264Cys)]

NM_015836.4(WARS2):c.791A>G (p.Tyr264Cys)

Gene:
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.791A>G (p.Tyr264Cys)
HGVS:
  • NC_000001.11:g.119033203T>C
  • NG_050658.1:g.112586A>G
  • NM_001378226.1:c.722A>G
  • NM_001378227.1:c.722A>G
  • NM_001378228.1:c.620A>G
  • NM_001378229.1:c.533A>G
  • NM_001378230.1:c.509A>G
  • NM_001378231.1:c.*126A>G
  • NM_015836.4:c.791A>GMANE SELECT
  • NM_201263.2:c.*157A>G
  • NP_001365155.1:p.Tyr241Cys
  • NP_001365156.1:p.Tyr241Cys
  • NP_001365157.1:p.Tyr207Cys
  • NP_001365158.1:p.Tyr178Cys
  • NP_001365159.1:p.Tyr170Cys
  • NP_056651.1:p.Tyr264Cys
  • NC_000001.10:g.119575826T>C
  • NM_015836.3:c.791A>G
Protein change:
Y170C
Links:
dbSNP: rs139194636
NCBI 1000 Genomes Browser:
rs139194636
Molecular consequence:
  • NM_001378231.1:c.*126A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_201263.2:c.*157A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001378226.1:c.722A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378227.1:c.722A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378228.1:c.620A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378229.1:c.533A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378230.1:c.509A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015836.4:c.791A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000265600HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha
criteria provided, single submitter

(HA_assertions_20161101)
Likely pathogenic
(Dec 10, 2015)
paternalresearch

Citation Link,

SCV001985777GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Uncertain significance
(Jun 26, 2023)
germlineclinical testing

Citation Link,

SCV003523346Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jun 28, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedpaternalyes1not providednot provided1not providedresearch

Citations

PubMed

Genomic diagnosis for children with intellectual disability and/or developmental delay.

Bowling KM, Thompson ML, Amaral MD, Finnila CR, Hiatt SM, Engel KL, Cochran JN, Brothers KB, East KM, Gray DE, Kelley WV, Lamb NE, Lose EJ, Rich CA, Simmons S, Whittle JS, Weaver BT, Nesmith AS, Myers RM, Barsh GS, Bebin EM, Cooper GM.

Genome Med. 2017 May 30;9(1):43. doi: 10.1186/s13073-017-0433-1.

PubMed [citation]
PMID:
28554332
PMCID:
PMC5448144

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000265600.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyes1not providednot provided1not providednot providednot provided

From GeneDx, SCV001985777.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28554332)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523346.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 264 of the WARS2 protein (p.Tyr264Cys). This variant is present in population databases (rs139194636, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of WARS2-related leukoencephalopathy (PMID: 28554332). ClinVar contains an entry for this variant (Variation ID: 224151). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024