Submissions for variant NM_001083961.2(WDR62):c.1535G>T (p.Arg512Leu)

dbSNP: rs375417358

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001974622	SCV002215795	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1435927). This variant has not been reported in the literature in individuals affected with WDR62-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 512 of the WDR62 protein (p.Arg512Leu). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WDR62 protein function. 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Fulgent Genetics, Fulgent Genetics	RCV002484665	SCV002778124	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2022-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001974622	SCV003805441	uncertain significance	not provided	2023-02-16	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; Has not been previously published as pathogenic or benign to our knowledge
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002484665	SCV005045236	uncertain significance	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations	2024-05-17	criteria provided, single submitter	curation	The heterozygous p.Arg512Leu variant in WDR62 was identified by our study, in the compound heterozygous state, along with a VUS, in one individual with primary microcephaly 2 with or without cortical malformations. The variant has been identified in 0.002% (27/1173580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs375417358)). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has been reported in ClinVar (Variation ID: 1435927) and has been interpreted as uncertain significance by three submitters. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg512Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).