Submissions for variant NM_006420.3(ARFGEF2):c.695G>A (p.Arg232His)

gnomAD frequency: 0.00009  dbSNP: rs140989375

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000385788	SCV000434263	uncertain significance	Periventricular heterotopia with microcephaly, autosomal recessive	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV000500597	SCV000593289	uncertain significance	not specified	2015-10-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000385788	SCV002767701	uncertain significance	Periventricular heterotopia with microcephaly, autosomal recessive	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_006420.2(ARFGEF2):c.695G>A in exon 6 of 39of the ARFGEF2 gene. This substitution is predicted to create a minor amino acid change from arginine to histidine at position 232 of the protein, NP_006411.2(ARFGEF2):p.(Arg232His). The arginine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (PDB, NCBI). In silico software predicts this variant to be tolerated (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.0072% (18 heterozygotes; 0 homozygotes). Alternative changes to cysteine and leucine at the same residue have also been reported in the gnomAD database at frequencies of 0.018% and 0.0004%, respectively. The variant has previously been reported as a VUS (ClinVar). A different variant in the same codon resulting in a change to cysteine has also been reported as a VUS (Decipher). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
Invitae	RCV002523161	SCV003280612	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 338681). This variant has not been reported in the literature in individuals affected with ARFGEF2-related conditions. This variant is present in population databases (rs140989375, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the ARFGEF2 protein (p.Arg232His).