Submissions for variant NM_005051.3(QARS1):c.1132C>T (p.Arg378Cys)

gnomAD frequency: 0.00001  dbSNP: rs185476065

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735295	SCV000854448	likely pathogenic	Insomnia; Seizure; Ectopic tissue; Cerebral visual impairment; Hypoplasia of the corpus callosum; Microcephaly; Strabismus; Abnormal nonverbal communicative behavior; Short foot; Profound global developmental delay; Small hand		criteria provided, single submitter	clinical testing
Invitae	RCV001299085	SCV001488162	uncertain significance	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the QARS protein (p.Arg378Cys). This variant is present in population databases (rs185476065, gnomAD 0.07%). This missense change has been observed in individuals with QARS-related conditions (PMID: 30755392, 31618474). ClinVar contains an entry for this variant (Variation ID: 598952). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on QARS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001592938	SCV001817031	likely pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on aminoacylation and QARS solubility (Chan et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with a second QARS variant on the opposite allele (in trans) in children with seizures, developmental delay, microcephaly, and brain malformations in published literature (Burgess et al., 2019; Chan et al., 2022; Ji et al., 2019); This variant is associated with the following publications: (PMID: 25471517, 34774383, 31618474, 30755392)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001299085	SCV002072546	likely pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2022-01-17	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_005051.3:c.1567C>T._x000D_ Criteria applied: PM3_STR, PM2_SUP, PP3
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156113	SCV003845335	likely pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411687	SCV004116042	likely pathogenic	QARS1-related condition	2023-02-18	criteria provided, single submitter	clinical testing	The QARS1 c.1132C>T variant is predicted to result in the amino acid substitution p.Arg378Cys. This variant has been reported in the compound heterozygous state in multiple individuals with epilepsy (Table S2 in Burgess et al. 2019. PubMed ID: 31618474; Table S2 in Ji et al. 2019. PubMed ID: 30755392; Chan et al. 2022. PubMed ID: 34774383). A functional study found that the p.Arg378Cys substitution decreases protein solubility (Chan et al. 2022. PubMed ID: 34774383). This variant is reported in 0.070% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-49137655-G-A). Given the evidence, we interpret c.1132C>T (p.Arg378Cys) as likely pathogenic.