Submissions for variant NM_003384.3(VRK1):c.858G>T (p.Met286Ile)

gnomAD frequency: 0.00051  dbSNP: rs139476915

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118846	SCV000153500	uncertain significance	not provided	2013-04-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322092	SCV000389784	uncertain significance	Pontocerebellar hypoplasia type 1A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000118846	SCV000576977	likely benign	not provided	2021-09-27	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000118846	SCV000611066	uncertain significance	not provided	2017-05-02	criteria provided, single submitter	clinical testing
Invitae	RCV000322092	SCV000639688	uncertain significance	Pontocerebellar hypoplasia type 1A	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 286 of the VRK1 protein (p.Met286Ile). This variant is present in population databases (rs139476915, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 130730). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000322092	SCV001526889	uncertain significance	Pontocerebellar hypoplasia type 1A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002444574	SCV002679911	uncertain significance	Inborn genetic diseases	2022-01-19	criteria provided, single submitter	clinical testing	The p.M286I variant (also known as c.858G>T), located in coding exon 9 of the VRK1 gene, results from a G to T substitution at nucleotide position 858. The methionine at codon 286 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488393	SCV004241074	uncertain significance	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: VRK1 c.858G>T (p.Met286Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 250858 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.43 fold of the estimated maximal expected allele frequency for a pathogenic variant in VRK1 causing Pontocerebellar Hypoplasia, Type 1A phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.858G>T has been reported in the literature in the compound heterozygous state in two siblings affected with distal spinal muscle atrophy (Demaegd_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; six submitters classified the variant as uncertain significance, one classified it as likely pathogenic, and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV003952580	SCV004776059	likely benign	VRK1-related condition	2022-08-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000559445	SCV001454663	uncertain significance	Congenital pontocerebellar hypoplasia type 1	2020-04-18	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000118846	SCV001922710	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118846	SCV001965772	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV002227063	SCV002505665	likely pathogenic	Distal spinal muscular atrophy	2020-10-01	no assertion criteria provided	clinical testing