Submissions for variant NM_001083961.2(WDR62):c.1480G>A (p.Gly494Arg)

gnomAD frequency: 0.00006  dbSNP: rs587784543

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147915	SCV000195407	likely pathogenic	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2013-05-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622916	SCV000741083	likely pathogenic	Inborn genetic diseases	2015-10-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000147915	SCV001287501	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507436	SCV001712986	likely pathogenic	not provided	2022-06-27	criteria provided, single submitter	clinical testing	PP1, PP4, PM2, PM3
GeneDx	RCV001507436	SCV001871094	uncertain significance	not provided	2022-02-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33604570)
Invitae	RCV001507436	SCV002210241	uncertain significance	not provided	2022-02-11	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 494 of the WDR62 protein (p.Gly494Arg). This variant is present in population databases (rs587784543, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Seckel syndrome (PMID: 33604570). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 160249). 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: "Probably Damaging"; 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.
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274918	SCV002562776	likely pathogenic	Abnormal cerebral morphology		no assertion criteria provided	clinical testing