ClinVar Miner

Submissions for variant NM_002887.4(RARS1):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00003  dbSNP: rs672601375
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000314506 SCV000330016 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The c.1 A>G pathogenic variant in the RARS gene 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). The pathogenic variant 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, the c.1 A>G variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.1 A>G to be a pathogenic variant."
Labcorp Genetics (formerly Invitae), Labcorp RCV000314506 SCV001387317 pathogenic not provided 2019-04-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Variants that affect the same initiator codon have been observed in individuals affected with clinical features of hypomyelinating leukodystrophy (PMID: 24777941, 27848944, 30791064, Invitae). ClinVar contains an entry for this variant (Variation ID: 162083). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the RARS mRNA. The next in-frame methionine is located at codon 73.
3billion RCV000149501 SCV002572755 pathogenic Hypomyelinating leukodystrophy 9 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Start-lost is reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alternate start codon. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24777941). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162083 / PMID: 24777941). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000149501 SCV000196141 pathogenic Hypomyelinating leukodystrophy 9 2014-04-29 no assertion criteria provided literature only

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