Submissions for variant NM_001083961.2(WDR62):c.1576G>A (p.Glu526Lys)

gnomAD frequency: 0.00022  dbSNP: rs147875659

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000000058	SCV000195410	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2014-05-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000489330	SCV000225557	uncertain significance	not provided	2015-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000489330	SCV000576907	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	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: 28756000, 20729831, 31130284, 31980526, 31258591, 21961505, 25303973, 24228726, 23065275, 34426522)
Illumina Laboratory Services, Illumina	RCV000000058	SCV000914841	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2018-10-17	criteria provided, single submitter	clinical testing	The WDR62 c.1576G>A (p.Glu526Lys) variant is a missense variant has been reported in one study, in which it is found in a homozygous state in one individual born to consanguineous Turkish parents, affected with microcephaly, intellectual disability, prognathism, dysconjugate gaze, and dysarthria (Bilg├╝var et al. 2010). The p.Glu526Lys variant was present in 3 of 1290 unrelated Turkish control chromosomes, absent from 1500 Caucasian control chromosomes, and is reported at a frequency of 0.000415 in the Other population of the Genome Aggregation Database. Based on the limited evidence, the p.Glu526Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for primary microcephaly 2 with or without cortical malformations. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000000058	SCV001523667	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2020-06-03	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000489330	SCV001712987	uncertain significance	not provided	2019-05-20	criteria provided, single submitter	clinical testing
Invitae	RCV000489330	SCV003275430	uncertain significance	not provided	2022-08-09	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 41). This missense change has been observed in individual(s) with primary microcephaly (PMID: 20729831, 31130284). This variant is present in population databases (rs147875659, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 526 of the WDR62 protein (p.Glu526Lys).
Ambry Genetics	RCV002512586	SCV003687735	uncertain significance	Inborn genetic diseases	2022-05-10	criteria provided, single submitter	clinical testing	The c.1576G>A (p.E526K) alteration is located in exon 12 (coding exon 12) of the WDR62 gene. This alteration results from a G to A substitution at nucleotide position 1576, causing the glutamic acid (E) at amino acid position 526 to be replaced by a lysine (K). (Bilgüvar, 2010), (Monies, 2019) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000000058	SCV003823722	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2021-04-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000000058	SCV004801176	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2024-03-14	criteria provided, single submitter	research
OMIM	RCV000000058	SCV000020201	pathogenic	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2010-09-09	flagged submission	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174806	SCV001338152	likely pathogenic	Autosomal recessive primary microcephaly	2023-02-07	flagged submission	clinical testing	Variant summary: WDR62 c.1576G>A (p.Glu526Lys) results in a conservative amino acid change located in the WD40-repeat-containing domain (IPR017986) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 285130 control chromosomes (gnomAD, Bilguvar_2010). c.1576G>A has been reported in the literature in at least two homozygous individuals affected with neurological malformations and intellectual disability (Bilguvar_2010, Monies_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.