Submissions for variant NM_020779.4(WDR35):c.2836G>A (p.Glu946Lys)

gnomAD frequency: 0.00005  dbSNP: rs779009587

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000312305	SCV000425989	uncertain significance	Cranioectodermal dysplasia 2	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.
Illumina Laboratory Services, Illumina	RCV000364596	SCV000425990	uncertain significance	Short-rib thoracic dysplasia 7 with or without polydactyly	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000312305	SCV005442674	uncertain significance	Cranioectodermal dysplasia 2		criteria provided, single submitter	clinical testing	The observed missense c.2836G>Ap.Glu946Lys variant in WDR35 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.005% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glu at position 946 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu946Lys in WDR35 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence Polyphen - Possibly Damaging, SIFT - Tolerated, and MutationTaster - Disease causing predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance.