ClinVar Miner

Submissions for variant NM_006295.3(VARS1):c.3650G>A (p.Arg1217His)

gnomAD frequency: 0.00051  dbSNP: rs368075745
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001330225 SCV001786609 uncertain significance Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2021-02-01 criteria provided, single submitter clinical testing The VARS1 c.3650G>A (p.Arg1217His) variant is a missense variant that has been reported in one study in which it was identified in a homozygous state in eight similarly affected individuals from a large consanguineous family and shown to segregate with disease (Alsemari et al. 2017). The proband from the family presented with tonic-clonic seizures from four months of age, with severe developmental delay, including a severe speech impairment, noted from one year of age. Severe growth hormone failure and skeletal abnormalities, including severe osteomalacia and multiple looser zones and fractures, microcephaly, scoliosis, and kyphosis were also noted. Brain MRI showed cerebellar atrophy however cortical abnormalities were not observed. The p.Arg1217His variant is reported at a frequency of 0.002360 in the African /African American population of the Genome Aggregation Database, a frequency that is higher than would be expected for a rare autosomal recessive disease. Homology modelling shows that residue Arg1217 is located within the C-terminal coiled-coil domain of VARS1 and is thought to play a role in the specific recognition of tRNA. The p.Arg1217His variant is predicted to abolish this function (Alsemari et al. 2017). Based on the available evidence and application of the ACMG criteria, the p.Arg1217His variant is classified as a variant of uncertain significance for neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.
New York Genome Center RCV001330225 SCV002506732 uncertain significance Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2021-06-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001330225 SCV003820352 uncertain significance Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2021-10-04 criteria provided, single submitter clinical testing
GeneDx RCV003153995 SCV003842576 uncertain significance not provided 2022-09-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29137650)
Baylor Genetics RCV001330225 SCV001521845 likely pathogenic Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy 2020-02-13 flagged submission clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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