ClinVar Miner

Submissions for variant NM_001083614.2(EARS2):c.328G>A (p.Gly110Ser) (rs201842633)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485250 SCV000565987 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The G110S variant in the EARS2 gene has been reported previously in association with infantile-onset 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). The G110S variant is observed in 61/119,420 (0.051%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The G110S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret G110S as a pathogenic variant
Institute of Human Genetics,Klinikum rechts der Isar RCV000033011 SCV000680195 pathogenic Combined oxidative phosphorylation deficiency 12 2017-12-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624375 SCV000742946 pathogenic Inborn genetic diseases 2017-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Illumina Clinical Services Laboratory,Illumina RCV000033011 SCV000915707 likely pathogenic Combined oxidative phosphorylation deficiency 12 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.
OMIM RCV000033011 SCV000056791 pathogenic Combined oxidative phosphorylation deficiency 12 2012-05-01 no assertion criteria provided literature only

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