Submissions for variant NM_003384.3(VRK1):c.706G>A (p.Val236Met)

dbSNP: rs771364038

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000203265	SCV000256752	pathogenic	Pontocerebellar hypoplasia type 1A	2013-10-14	criteria provided, single submitter	research	Segregates with the phenotype in affected family
GeneDx	RCV003441782	SCV000617743	pathogenic	not provided	2023-09-25	criteria provided, single submitter	clinical testing	Reported previously in trans with another VRK1 variant in two siblings with microcephaly and severe, rapidly progressive distal symmetric polyneuropathy with normal intellect (Gonzaga-Jauregui et al., 2013); Published functional studies demonstrate that the V236M variant results in loss of kinase activity (Martin-Doncel et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24970098, 27281532, 25609612, 26583493, 34169149, 30617279, 30847374, 31178479, 27149842, 35641352, 31560180, 31090908, 24126608, 31527692)
Invitae	RCV000203265	SCV000836197	pathogenic	Pontocerebellar hypoplasia type 1A	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 236 of the VRK1 protein (p.Val236Met). This variant is present in population databases (rs771364038, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of distal hereditary motor neuropathy (PMID: 24126608; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218924). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects VRK1 function (PMID: 31527692). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000203265	SCV002059512	likely pathogenic	Pontocerebellar hypoplasia type 1A	2020-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517363	SCV003566935	uncertain significance	Inborn genetic diseases	2021-12-16	criteria provided, single submitter	clinical testing	The c.706G>A (p.V236M) alteration is located in exon 8 (coding exon 7) of the VRK1 gene. This alteration results from a G to A substitution at nucleotide position 706, causing the valine (V) at amino acid position 236 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000203265	SCV002093696	uncertain significance	Pontocerebellar hypoplasia type 1A	2021-02-15	no assertion criteria provided	clinical testing
OMIM	RCV003387514	SCV004098884	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 10	2013-12-01	no assertion criteria provided	literature only