Submissions for variant NM_005051.3(QARS1):c.1543C>T (p.Arg515Trp)

gnomAD frequency: 0.00001  dbSNP: rs587777334

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437593	SCV000521311	likely pathogenic	not provided	2022-05-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as this variant disrupts aminoacylation activity, causing protein misfolding and aggregation (Zhang et al., 2014; Ognjenovi et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26869582, 24656866)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000114975	SCV002061643	pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2021-10-13	criteria provided, single submitter	clinical testing	PS3, PP3, PM1, PM2, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114975	SCV002282158	likely pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 515 of the QARS protein (p.Arg515Trp). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with progressive microcephaly with seizures and cerebral and cerebellar atrophy (PMID: 24656866). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127118). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects QARS function (PMID: 24656866). 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.
New York Genome Center	RCV000114975	SCV002548826	likely pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2021-08-13	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004764850	SCV005374828	pathogenic	Intellectual disability, autosomal dominant 43		criteria provided, single submitter	clinical testing	The observed missense c.1543C>T (p.Arg515Trp) variant in QARS1 gene has been reported in individuals affected with progressive microcephaly with seizures and cerebral and cerebellar atrophy (Zhang et al., 2014). Experimental studies demonstrate that this variant disrupts aminoacylation activity, causing protein misfolding and aggregation (Zhang et al., 2014; Ognjenović et al., 2016). This variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg515Trp in QARS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 515 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in QARS1 gene, the molecular diagnosis is not confirmed.
OMIM	RCV000114975	SCV000148896	pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2014-04-03	no assertion criteria provided	literature only