VCV000224791.45 - ClinVar

NM_006734.4(HIVEP2):c.2827C>T (p.Arg943Ter)

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.

(13)

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_006734.4(HIVEP2):c.2827C>T (p.Arg943Ter)

Variation ID: 224791 Accession: VCV000224791.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q24.2 6: 142771912 (GRCh38) [ NCBI UCSC ] 6: 143093049 (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	Apr 3, 2016	Oct 26, 2024	Oct 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006734.4:c.2827C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006725.3:p.Arg943Ter	nonsense
NC_000006.12:g.142771912G>A
NC_000006.11:g.143093049G>A
NG_047004.1:g.178290C>T

Protein change

R943*

Other names

Canonical SPDI

NC_000006.12:142771911: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: CA358404 OMIM: 143054.0002 dbSNP: rs869312841 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.
HIVEP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1005	1019

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.
Intellectual disability, autosomal dominant 43	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Oct 16, 2023	RCV000225218.15
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 17, 2022	RCV001092448.33

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 (Apr 06, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 43 Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Study: Clinvar_gadteam_Clinical_exome_analysis_3 Accession: SCV000803856.1 First in ClinVar: Jul 01, 2017 Last updated: Jul 01, 2017
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000266477.9 First in ClinVar: Apr 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26153216) (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 43 Affected status: yes Allele origin: germline	3billion Accession: SCV002058652.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:26153216 PMID:26153216 Comment: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more) Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000224791, PMID:26153216). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Brachycephaly (present) , Clinodactyly of the 5th finger (present) , Delayed speech and language development (present) , Generalized hypotonia (present) , Global developmental delay (present) … (more) Brachycephaly (present) , Clinodactyly of the 5th finger (present) , Delayed speech and language development (present) , Generalized hypotonia (present) , Global developmental delay (present) , Joint laxity (present) , Myopathy (present) , Elevated circulating creatine kinase concentration (present) (less)
Pathogenic (Nov 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 43 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580508.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS2, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: female
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818182.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Oct 16, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Intellectual disability, autosomal dominant 43 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004122951.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Publications: PubMed (1) PubMed: 36588750 Comment: Variant summary: HIVEP2 c.2827C>T (p.Arg943X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly … (more) Variant summary: HIVEP2 c.2827C>T (p.Arg943X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 249538 control chromosomes (gnomAD). c.2827C>T has been reported in the literature in at least one individual affected with Intellectual Disability, Autosomal Dominant 43, where it was found to be de novo (e.g. Quental_2022). These data suggest the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36588750). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 43 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236171.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (May 22, 2022)	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: SCV001587229.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 26153216‚ 27003583 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224791). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224791). This premature translational stop signal has been observed in individual(s) with intellectual disability (PMID: 26153216). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg943*) in the HIVEP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HIVEP2 are known to be pathogenic (PMID: 27003583). (less)
Pathogenic (May 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: SCV001248964.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Apr 20, 2022)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 43 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000282048.3 First in ClinVar: Jun 23, 2016 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 26153216 Comment on evidence: In a 4-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Srivastava et al. (2016) identified a de novo heterozygous c.2827C-T transition … (more) In a 4-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-43 (MRD43; 616977), Srivastava et al. (2016) identified a de novo heterozygous c.2827C-T transition (c.2827C-T, NM_006734.3) in exon 5 of the HIVEP2 gene, resulting in an arg943-to-ter (R943X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 2,500 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency of HIVEP2. (less)
Pathogenic (Oct 13, 2017)	no assertion criteria provided Method: provider interpretation	Intellectual disability, autosomal dominant 43 Affected status: yes Allele origin: de novo	GenomeConnect - Simons Searchlight Accession: SCV001443522.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-10-13 and interpreted as Pathogenic. The reporting laboratory … (more) Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-10-13 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Autistic behavior (present) , Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Strabismus (present) , Clumsiness (present) , Generalized hypotonia (present) , Cerebral palsy (present) , … (more) Autistic behavior (present) , Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Strabismus (present) , Clumsiness (present) , Generalized hypotonia (present) , Cerebral palsy (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Heart murmur (present) , Abnormality of the skeletal system (present) , Hip dysplasia (present) , Abnormality of the skin (present) , Keratosis pilaris (present) , Allergy (present) , Allergic rhinitis (present) , Abnormality of the cardiovascular system (present) (less) Age: 0-9 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2013-07-19 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Neonatal hypotonia (present) , Abnormality of vision (present) , Strabismus (present) , Clumsiness (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Otitis media … (more) Neonatal hypotonia (present) , Abnormality of vision (present) , Strabismus (present) , Clumsiness (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Otitis media (present) (less) Age: 0-9 years Sex: male Testing laboratory: Genome Diagnostics Laboratory, The Hospital for Sick Children Date variant was reported to submitter: 2016-04-18 Testing laboratory interpretation: Pathogenic
Pathogenic (Jan 29, 2019)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031326.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Intellectual disability, autosomal dominant 43 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091348.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
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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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26153216)

Comment:

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000224791, PMID:26153216). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Variant summary: HIVEP2 c.2827C>T (p.Arg943X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 249538 control chromosomes (gnomAD). c.2827C>T has been reported in the literature in at least one individual affected with Intellectual Disability, Autosomal Dominant 43, where it was found to be de novo (e.g. Quental_2022). These data suggest the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36588750). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224791). This premature translational stop signal has been observed in individual(s) with intellectual disability (PMID: 26153216). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg943*) in the HIVEP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HIVEP2 are known to be pathogenic (PMID: 27003583).

Comment:

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-10-13 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.

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
Expanding the Phenotypic Spectrum of HIVEP2-Related Intellectual Disability: Description of Two Portuguese Patients and Review of the Literature.	Quental R	Molecular syndromology	2022	PMID: 36588750
Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features.	Steinfeld H	Neurogenetics	2016	PMID: 27003583
Loss-of-function variants in HIVEP2 are a cause of intellectual disability.	Srivastava S	European journal of human genetics : EJHG	2016	PMID: 26153216

Text-mined citations for rs869312841 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_006734.4(HIVEP2):c.2827C>T (p.Arg943Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs869312841 ...