Submissions for variant NM_001083614.2(EARS2):c.1234C>T (p.Arg412Cys)

gnomAD frequency: 0.00002  dbSNP: rs549058278

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002554807	SCV003443542	likely pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 not expected to disrupt EARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 870561). This missense change has been observed in individual(s) with EARS2-related conditions (PMID: 27117034, 31665838). 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 (rs549058278, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 412 of the EARS2 protein (p.Arg412Cys).
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV001090120	SCV001245435	uncertain significance	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome		no assertion criteria provided	clinical testing