Submissions for variant NM_020745.4(AARS2):c.1774C>T (p.Arg592Trp)

gnomAD frequency: 0.00025  dbSNP: rs138119149

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196012	SCV000250992	pathogenic	not provided	2023-04-19	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: 25058219, 27251004, 27839525, 28822227, 21549344, 22277967, 24808023, 25705216, 29440775, 30952159, 31980526, 30819764, 31589614, 32938192, 33726816, 34088003)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000023929	SCV000680130	pathogenic	Combined oxidative phosphorylation defect type 8	2017-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622422	SCV000741177	pathogenic	Inborn genetic diseases	2022-03-25	criteria provided, single submitter	clinical testing	The c.1774C>T (p.R592W) alteration is located in exon 13 of the AARS2 gene. This alteration results from a C to T substitution at nucleotide position 1774, causing the arginine (R) at amino acid position 592 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.02% (64/282172) total alleles studied. The highest observed frequency was 0.04% (52/128596) of European (non-Finnish) alleles. This alteration is a recurrent pathogenic mutation reported in multiple unrelated patients and several siblings with a severe infantile mitochondrial hypertrophic cardiomyopathy phenotype (Götz, 2011; Taylor, 2014; Kamps, 2018). This amino acid position is not well conserved in available vertebrate species. The p.R592 amino acid is located in the editing domain of mtAlaRS. Protein modeling studies suggest that this residue is surface exposed and that may be involved in specific recognition and/or binding of mischarged mitochondrial tRNAAla in the editing domain (Gotz, 2011). Structural analysis predicts that this alteration will reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation (Euro, 2015). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Pediatric Genomics Discovery Program, Yale University	RCV000754863	SCV000882678	likely pathogenic	Pulmonary hypoplasia	2019-02-04	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000023929	SCV000967647	pathogenic	Combined oxidative phosphorylation defect type 8	2018-08-06	criteria provided, single submitter	clinical testing	The p.Arg592Trp variant in AARS2 has been reported in the homozygous or in the c ompound heterozygous state with loss-of-function or rare missense variants in 12 individuals with combined oxidative phosphorylation deficiency 8 with severe hy pertrophic cardiomyopathy, and segregated with disease in 1 affected family memb er (Gotz 2011, Calvo 2012, Taylor 2014, Euro 2015, Mazurova 2017, Kamps 2018). I t also segregated with disease in the affected twin siblings of two of the proba nds; however, it was not specified if these were identical or fraternal twins (E uro 2015, Kamps 2018). It has also been identified in 0.04% (48/126154) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org). Although this variant has been seen in the general population, it s frequency is low enough to be consistent with a recessive carrier frequency. C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein, though structural modeling sugges ts this variant may have an impact on protein function (Euro 2015). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessi ve combined oxidative phosphorylation deficiency 8 based on case observations, s egregation studies, and predicted impact on protein. ACMG/AMP criteria applied: ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP1.
CeGaT Center for Human Genetics Tuebingen	RCV000196012	SCV001246214	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000196012	SCV002019274	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV000196012	SCV002230847	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	This missense change is located in the editing domain of mitochondrial alanyl-tRNA synthetase and structural modeling suggests that this variant severely compromises aminoacylation activity (PMID: 25705216, 21549344, 25058219, 22277967). ClinVar contains an entry for this variant (Variation ID: 30940). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AARS2 protein function. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with infantile mitochondrial cardiomyopathy with combined oxidative phosphorylation deficiency (PMID: 21549344, 22277967, 25058219, 25705216). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs138119149, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 592 of the AARS2 protein (p.Arg592Trp).
3billion	RCV000023929	SCV002521291	pathogenic	Combined oxidative phosphorylation defect type 8	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030940). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:21549344, 22277967, 25058219, 25705216, 29440775). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 25058219, 25705216, 29440775). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000023929	SCV002768351	pathogenic	Combined oxidative phosphorylation defect type 8	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 8 (MIM#614096) and leukoencephalopathy, progressive, with ovarian failure (MIM#615889) (PMIDs: 28633377, 30285085, 24808023). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (64 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.R592Q: 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated editing domain (PMID: 25705216). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent founder mutation and has been reported as homozygous or compound heterozygous in multiple individuals with severe infantile cardiomyopathy (PMIDs: 21549344, 25058219, 25705216). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cytochrome c oxidase (COX) activity was severely reduced in heart and skeletal muscles of a deceased patient homozygous for the p.R592W variant. Blue-native electrophoresis of mitochondrial respiratory chain complexes demonstrated severely reduced COX and complex I (CI) in the heart, severe COX deficiency and CI reduction in the brain, and partial complex III deficiency in both tissues (PMID: 21549344). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_020745.3:c.647dupG ; p.Cys218Leufs*6) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, Heidelberg University	RCV000023929	SCV003936051	pathogenic	Combined oxidative phosphorylation defect type 8	2022-12-16	criteria provided, single submitter	clinical testing
OMIM	RCV000023929	SCV000045220	pathogenic	Combined oxidative phosphorylation defect type 8	2014-07-02	no assertion criteria provided	literature only