VCV000280509.51 - ClinVar

NM_001008537.3(NEXMIF):c.1441C>T (p.Arg481Ter)

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.

(10)

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.1441C>T (p.Arg481Ter)

Variation ID: 280509 Accession: VCV000280509.51

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.3 X: 74743116 (GRCh38) [ NCBI UCSC ] X: 73962951 (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	Sep 19, 2017	Oct 20, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001008537.3:c.1441C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001008537.1:p.Arg481Ter	nonsense
NC_000023.11:g.74743116G>A
NC_000023.10:g.73962951G>A
NG_027726.1:g.187337C>T

Protein change

R481*

Other names

Canonical SPDI

NC_000023.11:74743115:G:A

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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: CA10603638 OMIM: 300524.0007 dbSNP: rs886041701 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	1029	1168

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 7, 2023	RCV000361637.32
X-linked intellectual disability, Cantagrel type	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV000505390.14
not specified	Pathogenic (1)	criteria provided, single submitter	Sep 30, 2020	RCV004021068.1

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 (Jan 30, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330432.8 First in ClinVar: Dec 06, 2016 Last updated: Nov 11, 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: 27568816, 27358180, 33144681, 31175295, 35032046) (less)
Pathogenic (Sep 30, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000740833.5 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27358180 Comment: The c.1441C>T (p.R481) alteration, located in exon 3 (coding exon 2) of the KIAA2022 gene, consists of a C to T substitution at nucleotide position … (more) The c.1441C>T (p.R481) alteration, located in exon 3 (coding exon 2) of the KIAA2022 gene, consists of a C to T substitution at nucleotide position 1441. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 481. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. In one study, this mutation was detected in a nonverbal, nonambulatory female who also had intellectual disability, microcephaly, dysmorphic features, and hypotonia (de Lange, 2016). In our internal cohort, this variant occurred de novo in two females; one individual presented with epilepsy while the other presented with hypotonia, developmental delay, and dysmorphic features (Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jul 01, 2019)	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: SCV001247745.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (May 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability, Cantagrel type Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002526693.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Comment: This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2_MOD, PS4_MOD, PM2_SUP
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability, Cantagrel type (X-linked dominant inheritance) Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002586413.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022	Publications: PubMed (1) PubMed: 27358180 Sex: male
Pathogenic (Dec 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability, Cantagrel type (X-linked dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV002759356.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Clinical Features: Atypical behavior (present) , Delayed speech and language development (present) , Seizure (present) , Global developmental delay (present)
Pathogenic (Nov 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability, Cantagrel type Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018297.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 07, 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: SCV002245801.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 23615299‚ 27358180 Comment: This sequence change creates a premature translational stop signal (p.Arg481) 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.Arg481) 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 clinical features of NEXMIF-related conditions (PMID: 27358180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280509). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability, Cantagrel type Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV005045146.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Comment: The NEXMIF c.1441C>T (p.Arg481Ter) variant has been reported to occur de novo in at least one individual and has been described in at least three … (more) The NEXMIF c.1441C>T (p.Arg481Ter) variant has been reported to occur de novo in at least one individual and has been described in at least three families with intellectual disability, with both affected males and females described (de Lange IM et al., PMID: 27358180; Stamberger H et al., PMID: 33144681; Webster R et al., PMID: 27568816; Brea-Fern√°ndez AJ et al., PMID: 35322241). This variant has been reported in the ClinVar database as a germline pathogenic variant by nine submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
Pathogenic (Aug 20, 2021)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 98 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000599601.2 First in ClinVar: Sep 19, 2017 Last updated: Aug 24, 2021	Publications: PubMed (1) PubMed: 27358180 Comment on evidence: In a 2.5-year-old girl (patient 6) with X-linked intellectual developmental disorder-98 (XLID98; 300912), de Lange et al. (2016) identified a de novo heterozygous c.1441C-T transition … (more) In a 2.5-year-old girl (patient 6) with X-linked intellectual developmental disorder-98 (XLID98; 300912), de Lange et al. (2016) identified a de novo heterozygous c.1441C-T transition (c.1441C-T, NM_001008537.2) in the KIAA2022 gene, resulting in an arg481-to-ter (R481X) substitution. The mutation was not found in the ExAC database. The patient had a 100% skewed pattern of X-inactivation and no KIAA2022 expression. She did not have seizures. (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: 27568816, 27358180, 33144681, 31175295, 35032046)

Comment:

The c.1441C>T (p.R481*) alteration, located in exon 3 (coding exon 2) of the KIAA2022 gene, consists of a C to T substitution at nucleotide position 1441. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 481. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. In one study, this mutation was detected in a nonverbal, nonambulatory female who also had intellectual disability, microcephaly, dysmorphic features, and hypotonia (de Lange, 2016). In our internal cohort, this variant occurred de novo in two females; one individual presented with epilepsy while the other presented with hypotonia, developmental delay, and dysmorphic features (Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg481*) 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 clinical features of NEXMIF-related conditions (PMID: 27358180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280509). For these reasons, this variant has been classified as Pathogenic.

Comment:

The NEXMIF c.1441C>T (p.Arg481Ter) variant has been reported to occur de novo in at least one individual and has been described in at least three families with intellectual disability, with both affected males and females described (de Lange IM et al., PMID: 27358180; Stamberger H et al., PMID: 33144681; Webster R et al., PMID: 27568816; Brea-Fern√°ndez AJ et al., PMID: 35322241). This variant has been reported in the ClinVar database as a germline pathogenic variant by nine submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002586413.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 rs886041701 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001008537.3(NEXMIF):c.1441C>T (p.Arg481Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041701 ...