Submissions for variant NM_025216.3(WNT10A):c.511C>T (p.Arg171Cys)

gnomAD frequency: 0.00113  dbSNP: rs116998555

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490286	SCV000267561	uncertain significance	Odonto-onycho-dermal dysplasia; Tooth agenesis, selective, 4	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000255246	SCV000322009	likely pathogenic	not provided	2024-07-08	criteria provided, single submitter	clinical testing	Case-control studies suggest this variant is associated with tooth agenesis (PMID: 24043634); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28265457, 24312213, 30417976, 28981473, 29367877, 24700731, 31103801, 23167694, 34426522, 33034246, 34593752, 36071541, 35546689, 36553094, 36755192, 24311251, 24043634, 33329022, 37422997)
Illumina Laboratory Services, Illumina	RCV000335291	SCV000427550	benign	Odonto-onycho-dermal dysplasia	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000396415	SCV000427551	likely benign	Tooth agenesis, selective, 4	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000299227	SCV000427552	benign	SchC6pf-Schulz-Passarge syndrome	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490286	SCV001016930	benign	Odonto-onycho-dermal dysplasia; Tooth agenesis, selective, 4	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000335291	SCV001136220	uncertain significance	Odonto-onycho-dermal dysplasia	2019-05-28	criteria provided, single submitter	clinical testing
Stomatology Center, Xiangya Hospital, Central South University	RCV003233498	SCV003930328	pathogenic	Tooth agenesis, selective, 2		criteria provided, single submitter	research	We used whole exome sequencing to compare tooth loss gene loci between two brothers with hypophidrotic ectodermal dysplasia (HED), analyze the difference of tooth loss phenotype, and explore its mechanism. wes showed that an EDA mutation was found in both older and younger brothers (c.878T>G), and the compound heterozygous mutation of WNT10A (c.511C>T and c.637G>A) Found only in the elder brothers. Prediction of secondary and tertiary structures of the WNT10A variants (p. R171C, p.G213S) indicated the impaired function of the molecule. The elder brothers have a more severe tooth loss phenotype than younger brothers. It has been reported that eda c.878T>G mutation caused HED (PMID: 30526585). We believe that EDA is the main pathogenic gene in the two patients, and the complex heterozygous WNT10A missense mutation can aggravate the HED phenotype caused by EDA mutation, resulting in a severe edentulous mandible phenotype in the elder brother.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255246	SCV002033986	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255246	SCV002035055	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255246	SCV002037286	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255246	SCV002038432	uncertain significance	not provided		no assertion criteria provided	clinical testing
Department of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine	RCV000396415	SCV004028554	uncertain significance	Tooth agenesis, selective, 4		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734859	SCV005349483	uncertain significance	WNT10A-related disorder	2024-05-15	no assertion criteria provided	clinical testing	The WNT10A c.511C>T variant is predicted to result in the amino acid substitution p.Arg171Cys. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states in individuals with tooth agenesis (Song et al. 2014. PubMed ID: 24043634; Zeng et al. 2017. PubMed ID: 28981473; Park et al. 2019. PubMed ID: 31103801; Kanchanasevee et al. 2020. PubMed ID: 33329022). Also, this variant, in addition to a heterozygous variant in the EDA gene, has been reported in the heterozygous state in four individuals with non-syndromic and syndromic tooth agenesis (He et al. 2013. PubMed ID: 24312213). This variant was also reported, along with two other missense variants in WNT10A, in a patient with selective tooth agenesis (Family 8, II-1, Zhao et al. 2019. PubMed ID: 30417976). This variant, and another WNT10A missense variant, segregated with disease in that family and were both present in her affected father (Family 8, I-1, Zhao et al. 2019. PubMed ID: 30417976). However, this variant was also present in the heterozygous state in a patient with nonsyndromic tooth agenesis, but was also present in her unaffected sister and mother (Patient 4, Kanchanasevee et al. 2020. PubMed ID: 33329022). Reduced penetrance and variable expressivity due to heterozygous WNT10A variants has been reported (Song et al. 2014. PubMed ID: 24043634; Park et al. 2019. PubMed ID: 31103801; Kanchanasevee et al. 2020. PubMed ID: 33329022). In the gnomAD public population database this variant has been reported in 0.19% of alleles overall, including three homozygotes; it is reported in ~1.6% of alleles in the East Asian subpopulation. This variant has conflicting interpretations in ClinVar, ranging from benign to uncertain significance to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/225515/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.