Submissions for variant NM_001083614.2(EARS2):c.328G>A (p.Gly110Ser)

gnomAD frequency: 0.00025  dbSNP: rs201842633

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485250	SCV000565987	likely pathogenic	not provided	2022-12-16	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: 26741492, 26780086, 22492562, 28748214, 28748215, 26619324, 25854774, 25058219, 23008233, 31520968, 33962821, 31980526, 33128823)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000033011	SCV000680195	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2017-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624375	SCV000742946	pathogenic	Inborn genetic diseases	2021-06-25	criteria provided, single submitter	clinical testing	The c.328G>A (p.G110S) alteration is located in exon 3 (coding exon 3) of the EARS2 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the glycine (G) at amino acid position 110 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the EARS2 c.328G>A alteration was observed in 0.03% (69/265858) of total alleles studied, with a frequency of 0.05% (61/121100) in the European (non-Finnish) subpopulation. This alteration was previously reported in the compound heterozygous state with a second pathogenic EARS2 alteration in multiple patients with clinical features of mitochondrial glutamyl-tRNA synthetase deficiency and clinical severity ranging from the less severe disease course of developmental delay, abnormal brain MRI, childhood onset spasticity and seizures to a more severe disease course of fatal neonatal lactic acidosis (Steenweg, 2012; Danhauser, 2016; Prasun, 2019). The p.G110 amino acid is completely conserved in available vertebrate species. Functional studies in patient-derived skin fibroblasts have demonstrated decreased EARS2 protein levels and evidence of mitochondrial dysfunction including increased reactive oxygen species production and increased mitochondrial mass (Danhauser, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000033011	SCV000915707	likely pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2018-12-17	criteria provided, single submitter	clinical testing	The EARS2 c.328G>A (p.Gly110Ser) variant has been reported in two studies and is found in a total of three probands in a compound heterozygous state (Steenweg et al. 2012; Danhauser et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00061 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of proband fibroblasts revealed lower EARS2 protein levels and higher mitochondrial ROS when compared to control fibroblasts. Based on the collective evidence, the p.Gly110Ser variant is classified as likely pathogenic for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000033011	SCV002810333	likely pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2022-04-13	criteria provided, single submitter	clinical testing
Invitae	RCV000485250	SCV003443543	pathogenic	not provided	2023-06-24	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22492562). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. 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 EARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 39789). This variant is present in population databases (rs201842633, gnomAD 0.05%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 110 of the EARS2 protein (p.Gly110Ser).
Revvity Omics, Revvity	RCV000033011	SCV003831359	uncertain significance	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2021-08-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033011	SCV003844891	likely pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: EARS2 c.328G>A (p.Gly110Ser) results in a non-conservative amino acid change located in the Glutamyl/glutaminyl-tRNA synthetase, class Ib, catalytic domain (IPR020058) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 234458 control chromosomes (gnomAD). c.328G>A has been reported in the literature in individuals affected with EARS2 related disorders (example: Steenweg_2012 , Danhauser_2016, McNeil_2017, Prasun_2019). These data indicate that the variant is likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000033011	SCV004100338	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome		criteria provided, single submitter	clinical testing	The missense variant p.G110S in EARS2 (NM_001083614.2) has been reported previously in association with infantileonset mitochondrial encephalopathy when present in trans with another disease-causing variant in the EARS2 gene (Steenweg et al., 2012; Danhauser et al., 2016). Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species production, and altered mitochondrial morphology (Danhauser et al., 2016). This variant was found in ClinVar with a classification of Pathogenic/Likely Pathogenic. There is a small physicochemical difference between glycine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.G110S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 110 of EARS2 is conserved in all mammalian species. The nucleotide c.328 in EARS2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000033011	SCV004183557	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2023-10-13	criteria provided, single submitter	clinical testing
OMIM	RCV000033011	SCV000056791	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2012-05-01	no assertion criteria provided	literature only