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:: RCV000209945.8

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000265600	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20161101)	Likely pathogenic (Dec 10, 2015)	paternal	research	Citation Link,
SCV001985777	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 26, 2023)	germline	clinical testing	Citation Link,
SCV003523346	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 28, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28554332, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000265600

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha

criteria provided, single submitter

(HA_assertions_20161101)

Likely pathogenic
(Dec 10, 2015)

paternal

research

Citation Link,

SCV001985777

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 26, 2023)

germline

clinical testing

Citation Link,

SCV003523346

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 28, 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	paternal	yes	1	not provided	not provided	1	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

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

From GeneDx, SCV001985777.3

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

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

From Invitae, SCV003523346.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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 1, 2024

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