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

gnomAD frequency: 0.00007  dbSNP: rs200105202

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000239768	SCV000250986	pathogenic	not provided	2024-07-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25705216, 27734837, 29749055, 31920941, 31099476, 27749956, 31885218, 24808023, 31980526, 31589614, 33144682, 34784527, 35305867, 29971983, 30706699, 36732629, 38253606)
Eurofins Ntd Llc (ga)	RCV000239768	SCV000862734	pathogenic	not provided	2018-08-02	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001195936	SCV001366360	likely pathogenic	Combined oxidative phosphorylation defect type 8	2019-01-24	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5.
Baylor Genetics	RCV001195936	SCV001524648	likely pathogenic	Combined oxidative phosphorylation defect type 8	2019-09-30	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV001775096	SCV002012461	pathogenic	Generalized muscle weakness	2021-10-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000239768	SCV002019230	pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001808557	SCV002059713	pathogenic	Leukoencephalopathy, progressive, with ovarian failure	2020-05-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239768	SCV002149823	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs200105202, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213963). This missense change has been observed in individual(s) with leukoencephalopathy (PMID: 24808023, 27749956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the AARS2 protein (p.Arg199Cys).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001808557	SCV002576465	pathogenic	Leukoencephalopathy, progressive, with ovarian failure	2021-03-26	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3
Ambry Genetics	RCV002515373	SCV003707633	likely pathogenic	Inborn genetic diseases	2022-07-13	criteria provided, single submitter	clinical testing	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.
GenomeConnect, ClinGen	RCV001195936	SCV002075014	not provided	Combined oxidative phosphorylation defect type 8		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-10-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.