Submissions for variant NM_020779.4(WDR35):c.1636C>T (p.Arg546Cys)

gnomAD frequency: 0.00003  dbSNP: rs549077153

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000338739	SCV000426030	uncertain significance	Short rib-polydactyly syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000404364	SCV000426031	uncertain significance	Cranioectodermal dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV001850798	SCV002172452	uncertain significance	Cranioectodermal dysplasia 2; Short-rib thoracic dysplasia 7 with or without polydactyly	2022-07-03	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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 333391). This variant has not been reported in the literature in individuals affected with WDR35-related conditions. This variant is present in population databases (rs549077153, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 557 of the WDR35 protein (p.Arg557Cys).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470844	SCV002768439	uncertain significance	Short-rib thoracic dysplasia 7 with or without polydactyly	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3A. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 17). It is also present close to the intron-exon junction, and so has a potential effect on splicing. (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (8 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (38 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (P) 0508 – In silico predictions for abnormal splicing are conflicting. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - A comparable variant (histidine) has previously been described as variant of uncertain significance (LOVD). (N) 0804 - Variant has previously been described as variant of uncertain significance (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant, in the literature. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Ambry Genetics	RCV002521358	SCV003532568	uncertain significance	Inborn genetic diseases	2022-06-10	criteria provided, single submitter	clinical testing	The c.1669C>T (p.R557C) alteration is located in exon 17 (coding exon 17) of the WDR35 gene. This alteration results from a C to T substitution at nucleotide position 1669, causing the arginine (R) at amino acid position 557 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003226922	SCV003923581	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	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