Submissions for variant NM_001083614.2(EARS2):c.1547G>A (p.Arg516Gln)

gnomAD frequency: 0.00009  dbSNP: rs201727231

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254773	SCV000321576	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing	The R516Q variant has been previously published in association with leukoencephalopathy with thalmus and brainstem involvement and high lactate (LTBL) in a patient who was compound heterozygous for the two mutations (Steenweg et al., 2012). This patient was described as having a severe phenotype with hypotonia, impaired psychomotor development, dystonia, vision problems, elevated lactate, and seizures (Steenweg et al., 2012). The R516Q variant is a non-conservative amino acid substitution of a positively charged residue with an uncharged residue. We interpret this variant as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763375	SCV000894072	likely pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2022-01-14	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156088	SCV003845231	likely pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235167	SCV003934725	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: EARS2 c.1547G>A (p.Arg516Gln) results in a conservative amino acid change located in the Aminoacyl-tRNA synthetase, class I, anticodon-binding domain (IPR045462) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249576 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547G>A has been reported in the literature in compound heterozygous individuals affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (e.g., Steenweg_2012, Roux_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33128823, 33972171, 22492562). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic (n = 1) or likely pathogenic (n = 2). Additionally, another missense variant affecting the same amino acid, c.1546C>T (p.Arg516Trp), has been reported in the literature in patients affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (PMID: 27206875). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000763375	SCV004177099	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The EARS2 c.1547G>A (p.Arg516Gln) variant has been reported in two individuals affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (Roux CJ et al., PMID: 33972171; Steenweg ME et al., PMID: 22492562). One patient was compound heterozygous for c.1547G>A and a different pathogenic variant (Steenweg ME et al., PMID: 22492562). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.015% in European-non Finnish population. Another variant affecting codon 516, c.1546C>T (p.Arg516Trp), has been reported as pathogenic in two affected brothers (Sahin S et al., PMID: 27206875). An additional variant affecting codon 516, c.1546C>G (p.Arg516Gly), is reported in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 134876). Computational predictors are uncertain as to the impact of this variant on EARS2 function. This variant has been reported in the ClinVar database as pathogenic, likely pathogenic and as a variant of uncertain significance (ClinVar Variation ID:265109). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.