ClinVar Miner

Submissions for variant NM_006295.3(VARS1):c.3355C>T (p.Arg1119Cys)

gnomAD frequency: 0.00001  dbSNP: rs149378938
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Gleeson Lab, University of California San Diego - Department of Neuroscience RCV000754486 SCV000803742 likely pathogenic Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2018-01-01 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000754486 SCV001430791 likely pathogenic Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2020-05-28 criteria provided, single submitter research The homozygous p.Arg1119Cys variant in VARS1 was identified by our study in collaboration with the Gleeson Lab in an individual with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (PMID: 30755602). Please note that this variant may also be submitted to ClinVar by the Gleeson Lab. This variant was reported in 3 total Egyptian individuals with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, segregated with disease in 2 affected relatives from 1 family (PMID: 30755602), and has been identified in 0.007% (1/14966) of African chromosomes, 0.005% (1/18238) of East Asian chromosomes, and 0.005% (1/21226) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149378938). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 559839). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in affected homozygotes increases the likelihood that the p.Arg1119Cys variant is pathogenic (PMID: 30755602). Multiple variants with the same function as p.Arg1119Cys variant have been reported in association with disease in the literature and the variant is located in a region of VARS1 that is essential to protein function, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 30755602). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PM3 (Richards 2015).
OMIM RCV000754486 SCV000920572 pathogenic Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2019-08-20 no assertion criteria provided literature only

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