Submissions for variant NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu)

gnomAD frequency: 0.00044  dbSNP: rs139644798

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000256219	SCV001369637	likely pathogenic	Hypomyelinating leukodystrophy 9	2020-03-13	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_MOD,PS4_MOD,PM3,PP3.
CeGaT Center for Human Genetics Tuebingen	RCV001532053	SCV001747435	likely pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001532053	SCV002010047	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
3billion	RCV000256219	SCV002318718	likely pathogenic	Hypomyelinating leukodystrophy 9	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265854, PMID:28905880). In silico tool predictions suggest damaging effect of the variant on gene or gene product(3CNET: 0.777>=0.75). A missense variant is a common mechanism associated with Leukodystrophy, hypomyelinating, 9. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005004). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV001532053	SCV002508094	benign	not provided	2024-01-02	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000256219	SCV002556868	likely pathogenic	Hypomyelinating leukodystrophy 9	2021-04-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000256219	SCV002557765	likely pathogenic	Hypomyelinating leukodystrophy 9	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with hypomyelinating leukodystrophy, 9 (MIM#616140). Toxic gain of function has also been suggested (PMID: 31737794). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (119 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located adjacent in the annotated KMSKS motif, near a catalytic domain (PMID: 33515434, PMID: 28905880). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy. In one individual, the second variant was either due to a de novo event or non-paternity (PMID: 28905880, PMID: 31814314, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated protein mislocalization, increases in punctate structures and decreased phosphorylation of ribosomal S6 protein (PMID: 31737794), whereas transfected E.coli cells showed decreased aminoacetylation activity (PMID: 33515434). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000256219	SCV004037846	likely pathogenic	Hypomyelinating leukodystrophy 9	2023-06-14	criteria provided, single submitter	clinical testing	Variant summary: RARS c.1367C>T (p.Ser456Leu) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 244948 control chromosomes in the gnomAD database, including 2 homozygotes. c.1367C>T has been reported in the literature in compound heterozygous individuals affected with PelizaeusMerzbacher disease (Nafinisia_2017) or mild hypomyelinating leukodystrophy (Mendes_2020), and the former had a truncating variant in trans. These data indicate that the variant is likely associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced aminoacylation activity and phosphorylation of ribosomal S6 protein, as well as disrupting protein localization and formation of myelin structures (Matsumoto_2019, Li_2021). The following publications have been ascertained in the context of this evaluation (PMID: 28905880, 31814314, 33515434, 31737794). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=7) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV004021037	SCV004936903	uncertain significance	Inborn genetic diseases	2020-12-10	criteria provided, single submitter	clinical testing	The c.1367C>T (p.S456L) alteration is located in exon 12 (coding exon 12) of the RARS gene. This alteration results from a C to T substitution at nucleotide position 1367, causing the serine (S) at amino acid position 456 to be replaced by a leucine (L). This variant and a frameshift variant were identified in one individual with microcephaly, nystagmus, blindness, cognitive impairment, focal epilepsy, corpus callosum hypoplasia, and diffuse dysmyelination/hypomyelination of the central white matter; p.S456L was maternally inherited while the frameshift variant was not detected in either parent (Nafisinia, 2017). This variant was also identified with a another missense variant in a mildly affected individual with onset at two years of age and ability to walk without support; this individual did not have nystagmus, microcephaly, epilepsy, feeding difficulties, hypomyelination, or brain atrophy (Mendes, 2020). This variant formed punctate structures in 25% of cells compared wildtype in COS7 cells and failed to exhibit differentiated phenotypes with myelin web-like structures in FBD-102b cells (Matsumoto, 2019). The p.S456L alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV000256219	SCV005042670	likely pathogenic	Hypomyelinating leukodystrophy 9		criteria provided, single submitter	clinical testing	The missense c.1367C>T p.Ser456Leu variant in the RARS1 has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy Nafisinia, Michael et al.,2017. No published segregation evidence has been identified for this variant. This variant has moderate functional evidence supporting abnormal protein function Matsumoto, Naoto et al.,2019. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic/ Likely Pathogenic multiple submissions. The amino acid Serine at position 456 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser456Leu in RARS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000256219	SCV000322810	pathogenic	Hypomyelinating leukodystrophy 9		no assertion criteria provided	research
OMIM	RCV000256219	SCV000851997	pathogenic	Hypomyelinating leukodystrophy 9	2019-08-20	no assertion criteria provided	literature only