Submissions for variant NM_001083614.2(EARS2):c.320G>A (p.Arg107His)

gnomAD frequency: 0.00001  dbSNP: rs1021330566

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522647	SCV000617772	likely pathogenic	not provided	2017-10-25	criteria provided, single submitter	clinical testing	The R107H variant in the EARS2 gene has been reported previously in the compound heterozygous state along with another EARS2 variant in a few patients with infantile-onset mitochondrial encephalopathy (Steenweg et al., 2012; Danhauser et al., 2016). The R107H variant is not observed in large population cohorts (Lek et al., 2016). The R107H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R107H as a likely pathogenic variant.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578413	SCV000680196	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2017-12-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000522647	SCV001500065	likely pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000522647	SCV003443594	pathogenic	not provided	2022-08-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg107 amino acid residue in EARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26741492, 34440436). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters EARS2 gene expression (PMID: 26780086). 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 not expected to disrupt EARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 449533). This missense change has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 22492562, 26780086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 107 of the EARS2 protein (p.Arg107His).
Genetics and Molecular Pathology, SA Pathology	RCV000578413	SCV004175694	likely pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The EARS2 c.320G>A variant is a single nucleotide change in exon 3/9 of the EARS2 gene, which is predicted to change the amino acid arginine at position 107 in the protein to histidine. The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152250 sequenced alleles) (PM2). This variant has been detected in trans with another likely pathogenic variant NM_001083614.2:c.212del in this patient. This variant has also been reported twice in the literature in patients with neonatal hypoglycemia, severe lactic acidosis and corpus callosum agenesis: in trans with c.1A>G (PMID: 22492562) and c.328G>A / p.(Gly110Ser) (PMID: 26780086) (PM3_Strong). Functional studies in patient-derived fibroblasts demonstrated elevated ROS production in patient cells compared to several control cell lines, suggesting altered redox homeostasis (PMID: 26780086) (PS3_supporting). This variant is a novel missense change at an amino acid residue where a different likely pathogenic missense change has been seen before (c.319C>T; p.R107C) (PMID: 26741492) (PM5). The variant has been reported in dbSNP (rs1021330566) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 449533). It has been reported in HGMD (CM123408).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000578413	SCV005086789	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 12 (MIM#614924). (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 histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated tRNA synthetases class I (E and Q), catalytic domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic in ClinVar. It has also been reported in two compound heterozygous individuals with EARS2-related disorders in the literature (PMID: 22492562, 26780086). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. A clear decrease in EARS2 protein levels, increase in mitochondrial mass and an elevated ROS production was demonstrated in patient-derived fibroblast with this variant and a different EARS2 variant on the other allele (PMID: 26780086). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. p.(Arg107Cys) has previously been reported as likely pathogenic (ClinVar) however was not used as supporting evidence as this substitution constitutes are bigger amino acid change. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign