Submissions for variant NM_024678.6(NARS2):c.1253G>A (p.Arg418His)

gnomAD frequency: 0.00020  dbSNP: rs535877562

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000988619	SCV001138398	uncertain significance	Combined oxidative phosphorylation defect type 24	2024-11-25	criteria provided, single submitter	clinical testing	The NM_024678.6(NARS2):c.1253G>A (p.Arg418His) variant (rs535877562) has a GnomAD 4.1.0 frequency of 0.00004407 (71 heterozygotes) with no homozygotes. Comments from other ClinVar submissions and literature review (PMID: 31665838 and 35014173) result in a change to VUS.
Neuberg Centre For Genomic Medicine, NCGM	RCV000988619	SCV002073225	uncertain significance	Combined oxidative phosphorylation defect type 24		criteria provided, single submitter	clinical testing	The missense variant p.R418H in NARS2 (NM_024678.6) has been previously submitted to ClinVar as a Likely Pathogenic variant. However there is no assertion criteria or independent data available for review. It has not been observed in affected individuals in literature. The p.R418H variant is observed in 7/16,246 (0.0431%) alleles from individuals of African background in gnomAD Exomes and in 1/1,322 (0.0756%) alleles from individuals of African background in 1000 Genomes. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be damaging but the residue is weakly conserved across species. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858696	SCV002225115	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	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. 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 NARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 802711). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency and/or Leigh syndrome (PMID: 31665838, 35014173). This variant is present in population databases (rs535877562, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 418 of the NARS2 protein (p.Arg418His).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000988619	SCV003807871	uncertain significance	Combined oxidative phosphorylation defect type 24	2022-08-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 supporting, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702557	SCV005205245	uncertain significance	not specified	2024-06-06	criteria provided, single submitter	clinical testing	Variant summary: NARS2 c.1253G>A (p.Arg418His) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class II (D/K/N) domain (IPR004364) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251304 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NARS2 causing Combined Oxidative Phosphorylation Deficiency 24, allowing no conclusion about variant significance. c.1253G>A has been reported in the literature in the compound heterozygous state in at least one individual with clinical features of Combined Oxidative Phosphorylation Deficiency 24/Leigh Syndrome (e.g. Han_2019, Yang_2022, Stenton_2022) and in one individual with mitochondrial disease who also harbored a de novo variant in MT-TL1 (Wu_2023). These reports do not provide unequivocal conclusions about association of the variant with Combined Oxidative Phosphorylation Deficiency 24. 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: 31665838, 35094435, 36918699, 35014173). ClinVar contains an entry for this variant (Variation ID: 802711). Based on the evidence outlined above, the variant was classified as uncertain significance.