NM_006295.3(VARS1):c.3622C>T (p.Arg1208Ter) AND Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001095657.2

Allele description [Variation Report for NM_006295.3(VARS1):c.3622C>T (p.Arg1208Ter)]

NM_006295.3(VARS1):c.3622C>T (p.Arg1208Ter)

Gene:

VARS1:valyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.33

Genomic location:

Preferred name:

NM_006295.3(VARS1):c.3622C>T (p.Arg1208Ter)

HGVS:

NC_000006.12:g.31779071G>A
NG_028229.1:g.21865C>T
NM_006295.3:c.3622C>TMANE SELECT
NP_006286.1:p.Arg1208Ter
NC_000006.11:g.31746848G>A
NM_006295.2:c.3622C>T

Protein change:

R1208*

Links:

dbSNP: rs776596987

NCBI 1000 Genomes Browser:

rs776596987

Molecular consequence:

NM_006295.3:c.3622C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy
Identifiers:: MONDO: MONDO:0060621; MedGen: C4540493; OMIM: 617802

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001251413	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004122076	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001251413

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 1, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004122076

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 24, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Approach to Cohort-Wide Re-Analysis of Exome Data in 1000 Individuals with Neurodevelopmental Disorders.

Halfmeyer I, Bartolomaeus T, Popp B, Radtke M, Helms T, Hentschel J, Popp D, Jamra RA.

Genes (Basel). 2022 Dec 22;14(1). doi: 10.3390/genes14010030.

PubMed [citation]

PMID:: 36672771
PMCID:: PMC9858523

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001251413.1

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

Description

The variant was confirmed as compound heterozygous with a variant of uncertain significance (NM_006295.2: c.1014G>T).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122076.1

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

Description

Variant summary: VARS1 c.3622C>T (p.Arg1208X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.1e-05 in 243740 control chromosomes (gnomAD). c.3622C>T has been reported in the literature in an individual(s) affected with a Neurodevelopmental Disorder (Halfmeyer_2022). The following publication has been ascertained in the context of this evaluation (PMID: 36672771). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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: Nov 25, 2023

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