Submissions for variant NM_020779.4(WDR35):c.3193T>A (p.Cys1065Ser)

gnomAD frequency: 0.00006  dbSNP: rs200258619

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000368976	SCV000425973	uncertain significance	Cranioectodermal dysplasia 2	2018-01-12	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	RCV000272118	SCV000425974	uncertain significance	Short-rib thoracic dysplasia 7 with or without polydactyly	2018-01-12	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.
Invitae	RCV001861144	SCV002172610	uncertain significance	Cranioectodermal dysplasia 2; Short-rib thoracic dysplasia 7 with or without polydactyly	2022-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1076 of the WDR35 protein (p.Cys1076Ser). This variant is present in population databases (rs200258619, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with WDR35-related conditions. ClinVar contains an entry for this variant (Variation ID: 333370). 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"). 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.
Ambry Genetics	RCV002521354	SCV003702076	uncertain significance	Inborn genetic diseases	2022-04-27	criteria provided, single submitter	clinical testing	The c.3226T>A (p.C1076S) alteration is located in exon 27 (coding exon 27) of the WDR35 gene. This alteration results from a T to A substitution at nucleotide position 3226, causing the cysteine (C) at amino acid position 1076 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.