NM_024537.4(CARS2):c.84G>T (p.Trp28Cys) AND Combined oxidative phosphorylation defect type 27

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 5, 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:: RCV001297257.3

Allele description [Variation Report for NM_024537.4(CARS2):c.84G>T (p.Trp28Cys)]

NM_024537.4(CARS2):c.84G>T (p.Trp28Cys)

Genes:

LOC130010127:ATAC-STARR-seq lymphoblastoid silent region 5509 [Gene]
CARS2:cysteinyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q34

Genomic location:

Preferred name:

NM_024537.4(CARS2):c.84G>T (p.Trp28Cys)

HGVS:

NC_000013.11:g.110706010C>A
NG_042045.2:g.12592G>T
NM_001352252.2:c.-776+361G>T
NM_001352253.3:c.84G>T
NM_024537.2:c.84G>T
NM_024537.4:c.84G>TMANE SELECT
NP_001339182.1:p.Trp28Cys
NP_078813.1:p.Trp28Cys
NC_000013.10:g.111358357C>A
NG_042045.1:g.5171G>T
NR_147942.2:n.107G>T

Protein change:

W28C

Links:

dbSNP: rs1388391654

NCBI 1000 Genomes Browser:

rs1388391654

Molecular consequence:

NM_001352252.2:c.-776+361G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001352253.3:c.84G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024537.4:c.84G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_147942.2:n.107G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Combined oxidative phosphorylation defect type 27
Synonyms:: Combined oxidative phosphorylation deficiency 27
Identifiers:: MONDO: MONDO:0014728; MedGen: C5567608; OMIM: 616672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001486264	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001486264

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 5, 2022)

germline

clinical testing

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

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

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, SCV001486264.3

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

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 28 of the CARS2 protein (p.Trp28Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1001034). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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: Oct 14, 2023

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