Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000346910 | SCV000434285 | uncertain significance | Periventricular heterotopia with microcephaly, autosomal recessive | 2018-01-13 | 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. |
Gene |
RCV000414382 | SCV000491857 | uncertain significance | not provided | 2020-01-14 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
Invitae | RCV000414382 | SCV002118875 | uncertain significance | not provided | 2022-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1016 of the ARFGEF2 protein (p.Gly1016Arg). This variant is present in population databases (rs149644732, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ARFGEF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 338695). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. |
Victorian Clinical Genetics Services, |
RCV000346910 | SCV002767579 | uncertain significance | Periventricular heterotopia with microcephaly, autosomal recessive | 2020-05-25 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified, NM_006420.2(ARFGEF2):c.3046G>C in exon 22 of 39 of the ARFGEF2 gene. This substitution is predicted to create a major amino acid change from glycine to arginine at position 1016 of the protein, NP_006411.2(ARFGEF2):p.(Gly1016Arg). The glycine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain (PDB, NCBI). In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.025% (71 heterozygotes; 0 homozygotes. The variant has previously been reported as a VUS (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
Ambry Genetics | RCV002520016 | SCV003732989 | uncertain significance | Inborn genetic diseases | 2021-09-01 | criteria provided, single submitter | clinical testing | The c.3046G>C (p.G1016R) alteration is located in exon 22 (coding exon 22) of the ARFGEF2 gene. This alteration results from a G to C substitution at nucleotide position 3046, causing the glycine (G) at amino acid position 1016 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |