ClinVar Miner

Submissions for variant NM_002887.4(RARS1):c.2T>C (p.Met1Thr)

dbSNP: rs769713780
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440377 SCV000535157 pathogenic not provided 2016-12-15 criteria provided, single submitter clinical testing The c.2 T>C pathogenic variant in the RARS gene alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Additionally, another nucleotide substitution, c.1 A>G, that also affects the initiator Methionine codon has previously been reported in association with hypomyelinating leukodystrophy in an individual who was compound heterozygous for another variant in RARS (Wolf et al., 2014). Therefore we interpret c.2 T>C to be a pathogenic variant."
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000785104 SCV000923662 pathogenic Hypomyelinating leukodystrophy 9 2019-01-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000785104 SCV000992816 pathogenic Hypomyelinating leukodystrophy 9 2017-12-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000785104 SCV002808335 likely pathogenic Hypomyelinating leukodystrophy 9 2022-02-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV004659032 SCV005163115 pathogenic Inborn genetic diseases 2024-05-14 criteria provided, single submitter clinical testing The c.2T>C (p.M1?) alteration is located in coding exon 1 of the RARS1 gene and consists of a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in the homozygous state and/or in conjunction with other RARS1 variant(s) in individual(s) with features consistent with RARS1-related hypomyelinating leukodystrophy; however, clinical details were limited for one case (Liu, 2019; Rezaei, 2019). Based on the available evidence, this alteration is classified as pathogenic.

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