Submissions for variant NM_002887.4(RARS1):c.5A>G (p.Asp2Gly)

gnomAD frequency: 0.00003  dbSNP: rs672601372

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000149498	SCV001132579	pathogenic	Hypomyelinating leukodystrophy 9	2018-11-15	criteria provided, single submitter	research	The homozygous p.Asp2Gly variant in RARS was identified by our study in one individual with Hypomyelinating Leukodystrophy. This variant has been identified in the literature in the case of two affected homozygous siblings, one girl and one boy. It has also been identified in the case of three compound heterozygous affected probands, two sisters with the variants 45+1G>T, and one unrelated proband with the variant p.Cys32TrpfsTer39. Functional studies have shown that this variant causes severely reduced function of the protein complex (Nafisinia et al. 2017, PMID: 28905880; Wolf et al. 2014, PMID: 24777941). This variant has been identified in <0.01% (6/190228) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs672601372). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Hypomyelinating Leukodystrophy in an autosomal recessive manner based on in vitro functional studies and multiple reports of individuals with this variant and Hypomyelinating Leukodrystrophy in the literature.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228537	SCV002507989	pathogenic	not provided	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2 of the RARS protein (p.Asp2Gly). This variant is present in population databases (rs672601372, gnomAD 0.008%). This missense change has been observed in individual(s) with leukodystrophy (PMID: 24777941, 28905880). 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: 162080). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000149498	SCV000196138	pathogenic	Hypomyelinating leukodystrophy 9	2014-04-29	no assertion criteria provided	literature only
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000149498	SCV000298033	pathogenic	Hypomyelinating leukodystrophy 9		no assertion criteria provided	research