NM_006420.3(ARFGEF2):c.625G>A (p.Glu209Lys) AND Periventricular heterotopia with microcephaly, autosomal recessive

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jun 26, 2019
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000005353.18

Allele description [Variation Report for NM_006420.3(ARFGEF2):c.625G>A (p.Glu209Lys)]

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

Gene:

ARFGEF2:ADP ribosylation factor guanine nucleotide exchange factor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.13

Genomic location:

Preferred name:

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

HGVS:

NC_000020.11:g.48953577G>A
NG_011490.2:g.36840G>A
NM_006420.3:c.625G>AMANE SELECT
NP_006411.2:p.Glu209Lys
NC_000020.10:g.47570114G>A
NG_011490.1:g.36840G>A
NM_006420.2:c.625G>A
Q9Y6D5:p.Glu209Lys

Protein change:

E209K; GLU209LYS

Links:

UniProtKB: Q9Y6D5#VAR_037438; OMIM: 605371.0001; dbSNP: rs28937880

NCBI 1000 Genomes Browser:

rs28937880

Molecular consequence:

NM_006420.3:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Periventricular heterotopia with microcephaly, autosomal recessive (ARPHM)
Synonyms:: PERIVENTRICULAR NODULAR HETEROTOPIA 2; Heterotopia, periventricular, autosomal recessive; Periventricular heterotopia with microcephaly
Identifiers:: MONDO: MONDO:0011966; MedGen: C1842563; Orphanet: 2149; OMIM: 608097

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025531	OMIM	no assertion criteria provided	Uncertain significance (Jan 1, 2004)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 14647276, 27535533
SCV000267212	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 14647276, 25741868
SCV001159585	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jun 26, 2019)	germline	clinical testing	Citation Link,
SCV001302284	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 28, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001435235	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	research	PubMed (2) [See all records that cite these PMIDs] 14647276, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East Asian	germline	unknown	2	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Analysis of protein-coding genetic variation in 60,706 humans.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, et al.

Nature. 2016 Aug 18;536(7616):285-91. doi: 10.1038/nature19057.

PubMed [citation]

PMID:: 27535533
PMCID:: PMC5018207

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex.

Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA.

Nat Genet. 2004 Jan;36(1):69-76. Epub 2003 Nov 30.

PubMed [citation]

PMID:: 14647276

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000025531.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267212.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	2	not provided	not provided	reference population	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001159585.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001302284.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001435235.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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