VCV000242323.39 - ClinVar

NM_001008537.3(NEXMIF):c.652C>T (p.Arg218Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001008537.3(NEXMIF):c.652C>T (p.Arg218Ter)

Variation ID: 242323 Accession: VCV000242323.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.3 X: 74743905 (GRCh38) [ NCBI UCSC ] X: 73963740 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 3, 2016	Oct 20, 2024	Dec 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001008537.3:c.652C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001008537.1:p.Arg218Ter	nonsense
NC_000023.11:g.74743905G>A
NC_000023.10:g.73963740G>A
NG_027726.1:g.186548C>T

Protein change

R218*

Other names

Canonical SPDI

NC_000023.11:74743904:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10583970 dbSNP: rs758719615 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NEXMIF		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1014	1153

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 14, 2023	RCV000233744.38
Continuous spike and waves during slow sleep	Pathogenic (1)	criteria provided, single submitter	Sep 14, 2017	RCV001848017.10
X-linked intellectual disability, Cantagrel type	Pathogenic (1)	criteria provided, single submitter	Jul 16, 2021	RCV002494673.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 14, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Continuous spike and waves during slow-wave sleep syndrome Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000693461.2 First in ClinVar: Mar 04, 2018 Last updated: Dec 11, 2022	Comment: This de novo non-sense variant in the KIAA2022 (NEXMIF) gene was identified in a young female patient with epilepsy with CSWSS (continuous spike-waves during slow … (more) This de novo non-sense variant in the KIAA2022 (NEXMIF) gene was identified in a young female patient with epilepsy with CSWSS (continuous spike-waves during slow sleep) and mild global development delay (less) Age: 10-19 years Sex: female
Pathogenic (Apr 26, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000282079.13 First in ClinVar: Jul 03, 2016 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28135719, 29693785, 27568816, 27358180, 33504798, 33144681, 31785789) (less)
Pathogenic (Oct 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247751.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jul 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability, Cantagrel type Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002801022.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001390631.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23615299‚ 27358180‚ 29693785 Comment: This sequence change creates a premature translational stop signal (p.Arg218) in the NEXMIF gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg218) in the NEXMIF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXMIF are known to be pathogenic (PMID: 23615299). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with seizures and intellectual disability (PMID: 27358180, 29693785). ClinVar contains an entry for this variant (Variation ID: 242323). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28135719, 29693785, 27568816, 27358180, 33504798, 33144681, 31785789)

Comment:

This sequence change creates a premature translational stop signal (p.Arg218*) in the NEXMIF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXMIF are known to be pathogenic (PMID: 23615299). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with seizures and intellectual disability (PMID: 27358180, 29693785). ClinVar contains an entry for this variant (Variation ID: 242323). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature.	Lorenzo M	American journal of medical genetics. Part A	2018	PMID: 29693785
De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy.	de Lange IM	Journal of medical genetics	2016	PMID: 27358180
Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.	Van Maldergem L	Human molecular genetics	2013	PMID: 23615299

Text-mined citations for rs758719615 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001008537.3(NEXMIF):c.652C>T (p.Arg218Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs758719615 ...