NM_020745.4(AARS2):c.595C>T (p.Arg199Cys) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 13, 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:: RCV002515373.3

Allele description [Variation Report for NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)]

NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)

Genes:

POLR1C:RNA polymerase I and III subunit C [Gene - OMIM - HGNC]
AARS2:alanyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)

HGVS:

NC_000006.12:g.44311148G>A
NG_031952.1:g.7179C>T
NM_020745.4:c.595C>TMANE SELECT
NP_065796.2:p.Arg199Cys
NC_000006.11:g.44278885G>A
NM_020745.2:c.595C>T
NM_020745.3:c.595C>T
Q5JTZ9:p.Arg199Cys

Protein change:

R199C

Links:

UniProtKB: Q5JTZ9#VAR_071840; dbSNP: rs200105202

NCBI 1000 Genomes Browser:

rs200105202

Molecular consequence:

NM_020745.4:c.595C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003707633	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 13, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 24808023, 27734837, 27749956, 29749055, 29971983, 31099476, 31885218, 35305867 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003707633

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jul 13, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

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

Novel (ovario) leukodystrophy related to AARS2 mutations.

Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ, Salomons GS, Baruffini E, Melchionda L, Mariotti C, Strom TM, Meitinger T, Prokisch H, Chapman K, Colley A, Rocha H, Ounap K, Schiffmann R, Salsano E, Savoiardo M, Hamilton EM, Abbink TE, Wolf NI, et al.

Neurology. 2014 Jun 10;82(23):2063-71. doi: 10.1212/WNL.0000000000000497. Epub 2014 May 7.

PubMed [citation]

PMID:: 24808023
PMCID:: PMC4118500

Novel AARS2 gene mutation producing leukodystrophy: a case report.

Szpisjak L, Zsindely N, Engelhardt JI, Vecsei L, Kovacs GG, Klivenyi P.

J Hum Genet. 2017 Feb;62(2):329-333. doi: 10.1038/jhg.2016.126. Epub 2016 Oct 13.

PubMed [citation]

PMID:: 27734837

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV003707633.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The c.595C>T (p.R199C) alteration is located in exon 4 (coding exon 4) of the AARS2 gene. This alteration results from a C to T substitution at nucleotide position 595, causing the arginine (R) at amino acid position 199 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (26/282578) total alleles studied. The highest observed frequency was 0.02% (23/128984) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in trans with an AARS2 pathogenic mutation, in multiple individuals with mitochondrial alanyl-tRNA synthetase deficiency (Szpisjak, 2017; Carle, 2018; Lynch, 2016; Taglia, 2018; Srivastava, 2019; Xie, 2020; Cohen, 2022; Dallabona, 2014). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

#	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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