Submissions for variant NM_020779.4(WDR35):c.1183A>T (p.Asn395Tyr)

gnomAD frequency: 0.00135  dbSNP: rs143343508

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000395590	SCV000342726	uncertain significance	not provided	2016-06-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086026	SCV001021197	likely benign	Cranioectodermal dysplasia 2; Short-rib thoracic dysplasia 7 with or without polydactyly	2025-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001143732	SCV001304282	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	RCV001143733	SCV001304283	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000395590	SCV001470930	uncertain significance	not provided	2023-08-18	criteria provided, single submitter	clinical testing	The WDR35 c.1183A>T; p.Asn395Tyr variant (rs143343508) is reported in a fetus affected with short-rib polydactyly syndromes without biallelic pathogenic findings, no functional or segregation data were provided (Zhang 2018). This variant is also reported in ClinVar (Variation ID: 288569) and is found in the non-Finnish European population with an allele frequency of 0.27% (342/128,986 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.26). Due to limited information, the clinical significance of the p.Asn395Tyr variant is uncertain at this time. References: Zhang et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549.
CeGaT Center for Human Genetics Tuebingen	RCV000395590	SCV001501757	uncertain significance	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278315	SCV002567177	uncertain significance	Connective tissue disorder	2018-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782345	SCV005394965	likely benign	not specified	2024-09-11	criteria provided, single submitter	clinical testing	Variant summary: WDR35 c.1183A>T (p.Asn395Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251214 control chromosomes, predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in WDR35 causing WDR35-Related Disorders phenotype. c.1183A>T has been reported in the literature in individuals affected with short-rib polydactyly syndrome (Zhang_2018). These report(s) do not provide unequivocal conclusions about association of the variant with WDR35-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 288569). Based on the evidence outlined above, the variant was classified as likely benign.
Dan Cohn Lab, University Of California Los Angeles	RCV000515966	SCV000612115	uncertain significance	Short-rib thoracic dysplasia 6 with or without polydactyly	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515966	SCV001479551	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732829	SCV005345217	uncertain significance	WDR35-related disorder	2024-08-16	no assertion criteria provided	clinical testing	The WDR35 c.1183A>T variant is predicted to result in the amino acid substitution p.Asn395Tyr. This variant was reported in an individual with short rib-polydactyly syndrome (Table S3, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.27% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.