VCV000590334.9 - ClinVar

NM_001658.4(ARF1):c.296G>A (p.Arg99His)

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.

(7)

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/Likely 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_001658.4(ARF1):c.296G>A (p.Arg99His)

Variation ID: 590334 Accession: VCV000590334.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q42.13 1: 228097627 (GRCh38) [ NCBI UCSC ] 1: 228285328 (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	Nov 20, 2018	Oct 13, 2024	Sep 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001658.4:c.296G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001649.1:p.Arg99His	missense
NM_001024226.2:c.296G>A	NP_001019397.1:p.Arg99His	missense
NM_001024227.1:c.296G>A	NP_001019398.1:p.Arg99His	missense
NM_001024228.2:c.296G>A	NP_001019399.1:p.Arg99His	missense
NM_001658.3:c.296G>A
NC_000001.11:g.228097627G>A
NC_000001.10:g.228285328G>A

... more HGVS ... less HGVS

Protein change

R99H

Other names

Canonical SPDI

NC_000001.11:228097626: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

OMIM: 103180.0003 dbSNP: rs1558087712 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.
ARF1		-	-	GRCh38 GRCh37	1	76
LOC126806039	-	-	-	GRCh38	-	47

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.
Periventricular nodular heterotopia 8	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 22, 2024	RCV000721171.8
not provided	Uncertain significance (2)	no assertion criteria provided	-	RCV001579777.3

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 (Mar 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Periventricular nodular heterotopia 8 Affected status: yes Allele origin: de novo	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris Accession: SCV002104220.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 Comment: PS2, PS3, PS4, PM2, PP3, PP2	Secondary finding: no
Likely pathogenic (Dec 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Periventricular nodular heterotopia 8 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808382.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Periventricular nodular heterotopia 8 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086683.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 28868155‚ 36345169‚ 37185208 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, both gain of function and loss of function for missense variants have been described (PMIDs: 36345169, 37185208). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg99Cys) has been reported in one individual with speech delay (PMID: 37185208). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as a recurring, de novo variant in individuals with brain malformation with delayed myelination, neurodevelopmental abnormalities and/or speech delay with microcephaly and seizures (ClinVar, PMIDs: 36345169, 28868155, 37185208). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (Sep 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Periventricular nodular heterotopia 8 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005374493.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024
Pathogenic (Nov 13, 2018)	no assertion criteria provided Method: literature only	PERIVENTRICULAR NODULAR HETEROTOPIA 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000852086.1 First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018	Publications: PubMed (1) PubMed: 28868155 Comment on evidence: In a patient with periventricular nodular heterotopia-8 (PVNH8; 618185), Ge et al. (2016) identified a heterozygous c.296G-A transition (c.296G-A, NM_001024226) in the ARF1 gene resulting … (more) In a patient with periventricular nodular heterotopia-8 (PVNH8; 618185), Ge et al. (2016) identified a heterozygous c.296G-A transition (c.296G-A, NM_001024226) in the ARF1 gene resulting in an arg-to-his substitution at codon 99 (R99H). This variant occurred as a de novo event and was not seen in ExAC. Ge et al. (2016) reported that arginine-99 appears to contact 2 of the GDP-binding residues of ARF1. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808479.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959177.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, both gain of function and loss of function for missense variants have been described (PMIDs: 36345169, 37185208). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg99Cys) has been reported in one individual with speech delay (PMID: 37185208). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as a recurring, de novo variant in individuals with brain malformation with delayed myelination, neurodevelopmental abnormalities and/or speech delay with microcephaly and seizures (ClinVar, PMIDs: 36345169, 28868155, 37185208). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
ARF1-related disorder: phenotypic and molecular spectrum.	de Sainte Agathe JM	Journal of medical genetics	2023	PMID: 37185208
A neurodevelopmental disorder associated with an activating de novo missense variant in ARF1.	Ishida M	Human molecular genetics	2023	PMID: 36345169
Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.	Ge X	NPJ genomic medicine	2016	PMID: 28868155

Text-mined citations for rs1558087712 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001658.4(ARF1):c.296G>A (p.Arg99His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1558087712 ...