VCV000005050.25 - ClinVar

NM_006420.3(ARFGEF2):c.625G>A (p.Glu209Lys)

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006420.3(ARFGEF2):c.625G>A (p.Glu209Lys)

Variation ID: 5050 Accession: VCV000005050.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.13 20: 48953577 (GRCh38) [ NCBI UCSC ] 20: 47570114 (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	Oct 11, 2015	Feb 20, 2024	Jan 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006420.3:c.625G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006411.2:p.Glu209Lys	missense
NC_000020.11:g.48953577G>A
NC_000020.10:g.47570114G>A
NG_011490.2:g.36840G>A
	Q9Y6D5:p.Glu209Lys

... more HGVS ... less HGVS

Protein change

E209K

Other names

Canonical SPDI

NC_000020.11:48953576: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.

0.00419 (A)

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

The Genome Aggregation Database (gnomAD) 0.00079

Exome Aggregation Consortium (ExAC) 0.00151

The Genome Aggregation Database (gnomAD), exomes 0.00178

Trans-Omics for Precision Medicine (TOPMed) 0.00191

1000 Genomes Project 0.00419

1000 Genomes Project 30x 0.00437

Links

ClinGen: CA213135 UniProtKB: Q9Y6D5#VAR_037438 OMIM: 605371.0001 dbSNP: rs28937880 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.
ARFGEF2		-	-	GRCh38 GRCh37	682	709

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 heterotopia with microcephaly, autosomal recessive	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jun 26, 2019	RCV000005353.18
not specified	Likely benign (1)	criteria provided, single submitter	Oct 5, 2020	RCV000425899.4
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 15, 2024	RCV000710616.14

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.
Uncertain significance (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Periventricular heterotopia with microcephaly, autosomal recessive Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267212.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 14647276 Number of individuals with the variant: 2 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Uncertain significance (Jun 26, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Periventricular heterotopia with microcephaly, autosomal recessive Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159585.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020
Benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Periventricular heterotopia with microcephaly, autosomal recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001302284.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 14647276 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Periventricular heterotopia with microcephaly, autosomal recessive (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435235.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 14647276 Comment: The homozygous p.Glu209Lys variant in ARFGEF has been identified in at least 1 Turkish individual with consanguineous parents and periventricular heterotopia with microcephaly (PMID: 14647276, … (more) The homozygous p.Glu209Lys variant in ARFGEF has been identified in at least 1 Turkish individual with consanguineous parents and periventricular heterotopia with microcephaly (PMID: 14647276, 28333917). This variant has also been identified in >1% of Latino chromosomes and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive periventricular heterotopia with microcephaly. (less)
Benign (Dec 09, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000521221.5 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 24278701, 23755938, 14647276, 17850229, 20857375, 26765562, 27535533, 28333917)
Benign (Jan 15, 2024)	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: SCV001014932.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Oct 05, 2020)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000840859.2 First in ClinVar: Oct 20, 2018 Last updated: Sep 26, 2021	Publications: PubMed (3) PubMed: 27535533‚ 14647276‚ 12682315
Uncertain significance (Jan 01, 2004)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025531.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 27535533‚ 14647276 Comment on evidence: This variant, formerly titled PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE, has been reclassified based on the report of Lek et al. (2016). In affected members … (more) This variant, formerly titled PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE, has been reclassified based on the report of Lek et al. (2016). In affected members of a consanguineous Turkish family with autosomal recessive periventricular heterotopia with microcephaly (ARPHM; 608097), Sheen et al. (2004) identified a 625G-A transition in exon 6 of the ARFGEF2 gene, which produced a nonconservative amino acid substitution, glu209 to lys (E209K). Lek et al. (2016) noted that the E209K variant has a high allele frequency (0.0121) in the Latino population in the ExAC database, suggesting that it is not pathogenic. (less)

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

The homozygous p.Glu209Lys variant in ARFGEF has been identified in at least 1 Turkish individual with consanguineous parents and periventricular heterotopia with microcephaly (PMID: 14647276, 28333917). This variant has also been identified in >1% of Latino chromosomes and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive periventricular heterotopia with microcephaly.

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
Analysis of protein-coding genetic variation in 60,706 humans.	Lek M	Nature	2016	PMID: 27535533
Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex.	Sheen VL	Nature genetics	2004	PMID: 14647276
Autosomal recessive form of periventricular heterotopia.	Sheen VL	Neurology	2003	PMID: 12682315

Text-mined citations for rs28937880 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_006420.3(ARFGEF2):c.625G>A (p.Glu209Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28937880 ...