NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000210656.6

Allele description [Variation Report for NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)]

NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)

Gene:

VRK1:VRK serine/threonine kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.2

Genomic location:

Preferred name:

NM_003384.3(VRK1):c.1072C>T (p.Arg358Ter)

Other names:

NM_003384.3(VRK1):c.1072C>T; p.Arg358Ter

HGVS:

NC_000014.9:g.96876033C>T
NG_016293.1:g.83687C>T
NM_003384.3:c.1072C>TMANE SELECT
NP_003375.1:p.Arg358Ter
NC_000014.8:g.97342370C>T
NM_003384.2:c.1072C>T

Protein change:

R358*; ARG358TER

Links:

OMIM: 602168.0001; dbSNP: rs137853063

NCBI 1000 Genomes Browser:

rs137853063

Molecular consequence:

NM_003384.3:c.1072C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000263027	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 10, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19646678, 21920476, 24126608, 25356970, 27281532, 30108342, 31527692 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000263027

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 10, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene.

Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, King MC, Levy-Lahad E.

Am J Hum Genet. 2009 Aug;85(2):281-9. doi: 10.1016/j.ajhg.2009.07.006. Epub 2009 Jul 30.

PubMed [citation]

PMID:: 19646678
PMCID:: PMC2725266

Substrate profiling of human vaccinia-related kinases identifies coilin, a Cajal body nuclear protein, as a phosphorylation target with neurological implications.

Sanz-García M, Vázquez-Cedeira M, Kellerman E, Renbaum P, Levy-Lahad E, Lazo PA.

J Proteomics. 2011 Dec 21;75(2):548-60. doi: 10.1016/j.jprot.2011.08.019. Epub 2011 Sep 3.

PubMed [citation]

PMID:: 21920476

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000263027.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The c.1072C>T (p.R358*) alteration, located in exon 12 (coding exon 11) of the VRK1 gene, consists of a C to T substitution at nucleotide position 1072. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 358. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (16/250524) total alleles studied. The highest observed frequency was 0.149% (15/10058) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state and in trans with another VRK1 disease-causing mutation in multiple unrelated individuals with VRK1-related motor and sensory neuropathy with or without pontocerebellar hypoplasia (Renbaum, 2009; Farwell, 2015; Stoll, 2016; Gonzaga-Jauregui, 2013; Reches, 2018; Ambry internal data). Functional studies suggest that this alteration demonstrates mislocalization, reduced protein stability and reduced kinase activity (Martin-Doncel, 2019; Sanz-Garcia, 2011). Based on the available evidence, this alteration is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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