ClinVar Miner

Submissions for variant NM_001083614.2(EARS2):c.949G>T (p.Gly317Cys)

gnomAD frequency: 0.00013  dbSNP: rs746838793
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000286269 SCV000396059 uncertain significance Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome 2017-04-27 criteria provided, single submitter clinical testing The EARS2 c.949G>T (p.Gly317Cys) missense variant has been reported in one study in which it was found in a compound heterozygous state with a second missense variant in one patient who presented with a mild form of combined oxidative phosphorylation deficiency based on disease course and MRI findings (Steenweg et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00115 in the Latino population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Gly317Cys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV002521003 SCV003441831 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing 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: 318550). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22492562, 28973083, 33855712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs746838793, gnomAD 0.06%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 317 of the EARS2 protein (p.Gly317Cys).

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