NM_020779.4(WDR35):c.1889T>G (p.Leu630Ter) AND WDR35-related disorder

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000288028.7

Allele description [Variation Report for NM_020779.4(WDR35):c.1889T>G (p.Leu630Ter)]

NM_020779.4(WDR35):c.1889T>G (p.Leu630Ter)

Gene:

WDR35:WD repeat domain 35 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p24.1

Genomic location:

Preferred name:

NM_020779.4(WDR35):c.1889T>G (p.Leu630Ter)

HGVS:

NC_000002.12:g.19941796A>C
NG_021212.1:g.53328T>G
NM_001006657.2:c.1922T>G
NM_020779.4:c.1889T>GMANE SELECT
NP_001006658.1:p.Leu641Ter
NP_065830.2:p.Leu630Ter
NC_000002.11:g.20141557A>C
NM_001006657.1:c.1922T>G
p.Leu641X

Protein change:

L630*; LEU641TER

Links:

OMIM: 613602.0015; dbSNP: rs199952377

NCBI 1000 Genomes Browser:

rs199952377

Molecular consequence:

NM_001006657.2:c.1922T>G - nonsense - [Sequence Ontology: SO:0001587]
NM_020779.4:c.1889T>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: WDR35-related disorder
Synonyms:: WDR35-Related Disorders; WDR35-related condition
Identifiers:: MedGen: CN239419

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000426023	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22486404, 25914204 Citation Link,
SCV005039172	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000426023

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Apr 27, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV005039172

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 25, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel WDR35 mutations in patients with cranioectodermal dysplasia (Sensenbrenner syndrome).

Hoffer JL, Fryssira H, Konstantinidou AE, Ropers HH, Tzschach A.

Clin Genet. 2013 Jan;83(1):92-5. doi: 10.1111/j.1399-0004.2012.01880.x. Epub 2012 Apr 9. No abstract available.

PubMed [citation]

PMID:: 22486404

Respiratory motile cilia dysfunction in a patient with cranioectodermal dysplasia.

Li Y, Garrod AS, Madan-Khetarpal S, Sreedher G, McGuire M, Yagi H, Klena NT, Gabriel GC, Khalifa O, Zahid M, Panigrahy A, Weiner DJ, Lo CW.

Am J Med Genet A. 2015 Sep;167A(9):2188-96. doi: 10.1002/ajmg.a.37133. Epub 2015 Apr 25.

PubMed [citation]

PMID:: 25914204

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000426023.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The WDR35 c.1922T>G (p.Leu641Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in two individuals with cranioectodermal dysplasia, both in a compound heterozygous state with a missense variant (Hoffer et al. 2013; Li et al. 2015). The variant was absent from 300 control chromosomes but is reported at a frequency of 0.00039 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Leu641Ter variant is classified as likely pathogenic for WDR35-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005039172.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: WDR35 c.1922T>G (p.Leu641X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 218956 control chromosomes. c.1922T>G has been reported in the literature in individuals affected with WDR35-Related Disorders (Li_2015). These data do not allow any conclusion about variant significance. 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: 25914204). ClinVar contains an entry for this variant (Variation ID: 65619). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 22, 2024

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