VCV000004462.85 - ClinVar

NM_025216.3(WNT10A):c.682T>A (p.Phe228Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(28)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(15); Likely pathogenic(2); Pathogenic, low penetrance(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_025216.3(WNT10A):c.[487C>T];[682T>A]

Identifiers

NM_025216.3(WNT10A):c.682T>A (p.Phe228Ile)

Variation ID: 4462 Accession: VCV000004462.85

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218890289 (GRCh38) [ NCBI UCSC ] 2: 219755011 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Nov 24, 2024	Oct 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025216.3:c.682T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079492.2:p.Phe228Ile	missense
NC_000002.12:g.218890289T>A
NC_000002.11:g.219755011T>A
NG_012179.1:g.14757T>A
	Q9GZT5:p.Phe228Ile

... more HGVS ... less HGVS

Protein change

F228I

Other names

Canonical SPDI

NC_000002.12:218890288:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00599 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00578

1000 Genomes Project 0.00599

Exome Aggregation Consortium (ExAC) 0.01273

The Genome Aggregation Database (gnomAD), exomes 0.01392

The Genome Aggregation Database (gnomAD) 0.01450

Trans-Omics for Precision Medicine (TOPMed) 0.01462

Links

ClinGen: CA116867 UniProtKB: Q9GZT5#VAR_062511 OMIM: 606268.0003 dbSNP: rs121908120 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
WNT10A		-	-	GRCh38 GRCh37	513	567

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Odonto-onycho-dermal dysplasia	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Apr 12, 2023	RCV000004717.26
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000255788.41
Tooth agenesis, selective, 4	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 10, 2024	RCV000445356.23
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 25, 2024	RCV000622932.13
Odonto-onycho-dermal dysplasia Tooth agenesis, selective, 4	Pathogenic, low penetrance (1)	criteria provided, single submitter	Jan 31, 2024	RCV000550721.15
Hypohidrotic ectodermal dysplasia	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 12, 2023	RCV000754840.11
Tooth agenesis	Pathogenic (1)	no assertion criteria provided	Sep 15, 2014	RCV000845113.9
Odonto-onycho-dermal dysplasia SchC6pf-Schulz-Passarge syndrome Tooth agenesis, selective, 4	Pathogenic (3)	criteria provided, single submitter	Mar 22, 2023	RCV001535660.13
Ectodermal dysplasia	Pathogenic (2)	criteria provided, single submitter	Jul 1, 2023	RCV001729336.11
SchC6pf-Schulz-Passarge syndrome Tooth agenesis, selective, 4	Pathogenic (1)	criteria provided, single submitter	Aug 27, 2021	RCV001813948.12
WNT10A-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 23, 2024	RCV004528071.2
See cases	Pathogenic (1)	criteria provided, single submitter	Jan 17, 2017	RCV004584315.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Mar 12, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tooth agenesis, selective, 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001736849.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Number of individuals with the variant: 1 Clinical Features: Epicanthus (present) , High forehead (present) , Hypotelorism (present) , Amblyopia (present) , Partial congenital absence of teeth (present) , Eruption failure (present) , Hypotonia … (more) Epicanthus (present) , High forehead (present) , Hypotelorism (present) , Amblyopia (present) , Partial congenital absence of teeth (present) , Eruption failure (present) , Hypotonia (present) , Intellectual disability, mild (present) , Ventricular septal defect (present) , Pes cavus (present) , Short foot (present) , Hallux valgus (present) , Deep philtrum (present) , Clinodactyly of the 5th finger (present) , Prominent nasal tip (present) , Small hand (present) (less) Age: 10-19 years Sex: female Ethnicity/Population group: Caucasians Tissue: blood
Uncertain significance (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Odonto-onycho-dermal dysplasia Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737316.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Pathogenic (May 27, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Odonto-onycho-dermal dysplasia Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136221.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 04, 2022
Pathogenic (Jun 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tooth agenesis, selective, 4 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579112.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM3, PP1_MOD, PM2_SUP, PP3	Number of individuals with the variant: 7 Sex: female
Pathogenic (Mar 22, 2023)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	SchC6pf-Schulz-Passarge syndrome Odonto-onycho-dermal dysplasia Tooth agenesis, selective, 4 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: inherited	New York Genome Center Accession: SCV004046548.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Observation 1: Clinical Features: Chronic sinusitis (present) , Recurrent ear infections (present) , Recurrent respiratory infections (present) , Type 2 diabetes mellitus (present) , Hypothyroidism (present) , Peripheral neuropathy … (more) Chronic sinusitis (present) , Recurrent ear infections (present) , Recurrent respiratory infections (present) , Type 2 diabetes mellitus (present) , Hypothyroidism (present) , Peripheral neuropathy (present) (less) Secondary finding: no Observation 2: Clinical Features: Recurrent infections (present) , Decreased circulating IgG concentration (present) Secondary finding: no
Likely pathogenic (May 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tooth agenesis, selective, 4 Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175284.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (2) PubMed: 25713620‚ 29364747 Comment: The WNT10A c.682T>A variant is classified as LIKELY PATHOGENIC (low penetrance) (PP3, PS3, PS4) The WNT10A c.682T>A variant is a single nucleotide change in exon … (more) The WNT10A c.682T>A variant is classified as LIKELY PATHOGENIC (low penetrance) (PP3, PS3, PS4) The WNT10A c.682T>A variant is a single nucleotide change in exon 3 of the WNT10A gene, which is predicted to change the amino acid phenylalanine at position 228 in the protein to isoleucine. This variant has been reported in a heterozygous state in many individuals with isolated hypodontia or oligodontia, as well as in unaffected carriers and is therefore considered to be a pathogenic variant with low penetrance. Although the population frequency is high (approximately 1.37%), the incidence of this dental agenesis is significantly higher (approximately 6.75%) (PMID:25713620) (PS4). Large meta analysis shows 2.25 - 3.42 fold increased risk for isolated tooth agenesis (PMID:29364747) (PS3). This variant has conflicting reports of pathogenicity in ClinVar, although the majority of other diagnostic laboratories classify it as pathogenic (ClinVar Variation ID: 19501). This variant has been reported as damaging in HGMD (CM094237). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
Pathogenic (Sep 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypohidrotic ectodermal dysplasia (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540673.2 First in ClinVar: Apr 09, 2017 Last updated: Apr 20, 2024	Publications: PubMed (7) PubMed: 24700731‚ 19559398‚ 22581971‚ 24449199‚ 23401279‚ 23167694‚ 21484994 Comment: The p.Phe228Ile variant in WNT10A has been reported in over 50 individuals with clinical features of ectodermal dysplasia or isolated tooth agenesis (hypodontia) in the … (more) The p.Phe228Ile variant in WNT10A has been reported in over 50 individuals with clinical features of ectodermal dysplasia or isolated tooth agenesis (hypodontia) in the homozygous or compound heterozygous state. It has also been seen in the heterozygous state in individuals with tooth agenesis with or without some features of ectodermal dysplasia as well as in asymptomatic family members. This variant segregated with disease in at least 17 affected individuals from multiple families (Bohring 2009 PMID: 19559398, Kantaputra 2011 PMID: 21484994, van den Boogaard 2012 PMID: 22581971, Mostowska 2013 PMID: 23167694, Plaisancie 2013 PMID: 23401279, Arzoo 2013 PMID: 24449199, Mues 2014 PMID: 24700731). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 4462) and has been identified in 3.5% (120/3470) of Ashkenazi Jewish and 2.2% (1515/67998) of European chromosomes, including many homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). However, studies have consistently found that it is in a significantly higher proportion of tooth agenesis cohorts than control cohorts (Bohring 2009 PMID: 19559398, Arzoo 2013 PMID: 24449199, Mues 2014 PMID: 24700731). In a large meta-analysis, this variant was associated with a 2.25-3.42-fold risk (95% CI: 1.39-4.10) for isolated tooth agenesis, the autosomal dominant condition associated with WNT10A (Jonsson 2018 PMID: 29364747). This variant is thought to have lower penetrance with variable expressivity, as heterozygotes for this variant were either asymptomatic or had hypodontia and/or mild clinical features of ectodermal dysplasia (Bohring 2009 PMID: 19559398). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for clinical features of ectodermal dysplasia, ranging from isolated tooth agenesis with or without other clinical features in the heterozygous state to a classic ectodermal dysplasia phenotype in the homozygous or compound heterozygous state. However, this variant is associated with a lower penetrant disease compared to other pathogenic variants in the WNT10A gene. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PP3. (less)
Pathogenic (Jan 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002506441.2 First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PS4,PS5,PP3,PP4,PP5 Number of individuals with the variant: 1 Clinical Features: Oligodontia (present) Age: 10-19 years Sex: male Tissue: blood
Pathogenic (Aug 29, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypohidrotic ectodermal dysplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Breda Genetics srl Accession: SCV000882567.1 First in ClinVar: Feb 11, 2019 Last updated: Feb 11, 2019	Comment: This variant has been identified in an individual with congenital alopecia, hypodontia, and hypohidrosis. In the family, inheritance was compatible with a dominant pattern. This … (more) This variant has been identified in an individual with congenital alopecia, hypodontia, and hypohidrosis. In the family, inheritance was compatible with a dominant pattern. This nonsynonymous variant is reported with an estimated allele frequency of 0.014 in gnomAD exomes, 0.01215 in gnomAD genomes, and 0.019 in NHLI Exome Sequencing Project (ESP). The nucleotide position is conserved across 35 mammalian species (GERP RS: 4.46). In silico analysis indicates that the variant might be damaging (MutationTaster: disease-causing; FATHMM-MKL: damaging; Provean: damaging; DANN: 0.992). The p.Phe228Ile mutation represents the most common allele identified in cases with isolated hypodontia (PMIDs: 22581971, 24449199, 24700731). Reduced penetrance and variable expressivity have been reported in carriers of the p.Phe228Ile mutation. Nearly half of heterozygotes may display mild multifocal symptoms, such as variable abnormalities of skin, hair, teeth or nails (PMIDs: 19559398, 21279306). For instance, van den Boogaard et al. (PMID: 22581971) reported a p.Phe228Ile heterozygote presenting with hypodontia, alopecia, hypohidrosis and mild nail dysplasia. Autosomal dominant inheritance of isolated hypodontia-microdontia in p.Phe228Ile heterozygotes has been described also by Kantaputra and Sripathomsawat (PMID: 21484994). (less) Clinical Features: Partial congenital absence of teeth (present) , Alopecia (present) , Hypohidrosis (present) , Hypohidrotic ectodermal dysplasia (present) Sex: female
Pathogenic (Jul 27, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322010.7 First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019	Comment: One of the most common pathogenic variants reported in this gene associated with semi-dominant ectodermal dysplasia with variable expressivity; Observed in the heterozygous state in … (more) One of the most common pathogenic variants reported in this gene associated with semi-dominant ectodermal dysplasia with variable expressivity; Observed in the heterozygous state in individuals with isolated hypodontia or oligodontia, in individuals with other features of ectodermal dysplasia, and also in unaffected carriers (Bohring et al., 2009; Kantaputra et al., 2011; Cluzeau et al., 2011; van den Boogaard et al., 2012; Mostowska et al., 2013; Plaisancie et al., 2013; Tardieu et al., 2017); Case control studies suggest this variant is associated with hypodontia (van den Boogaard et al., 2012); 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: 21484994, 20301291, 23401279, 22581971, 24700731, 23167694, 24398796, 24123366, 25333069, 21228398, 24702986, 23991204, 25629078, 19559398, 28105635, 20979233, 27881089, 26049155, 25545742, 26087098, 28813618, 28976000, 29364747, 29364501, 29431110, 24449199, 21279306, 30046887, 30426266, 31798653, 32618450, 31618753, 33144682) (less)
Pathogenic (Aug 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SchC6pf-Schulz-Passarge syndrome Tooth agenesis, selective, 4 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061543.2 First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022	Comment: PM3_Strong, PP1, PP3
Pathogenic (Feb 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tooth agenesis, selective, 4 Affected status: yes Allele origin: germline	DASA Accession: SCV002097280.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Publications: PubMed (11) PubMed: 30974434‚ 30426266‚ 29364747‚ 28976000‚ 28813618‚ 27881089‚ 24700731‚ 22581971‚ 21279306‚ 20979233‚ 21484994 Comment: The c.682T>A;p.(Phe228Ile) missense variant has been observed in affected individual(s) (PMID: 30974434; 30426266; 29364747; 28976000; 28813618; 27881089; 24700731; 22581971; 21279306; 20979233; 21484994) - PS4.The p.(Phe228Ile) … (more) The c.682T>A;p.(Phe228Ile) missense variant has been observed in affected individual(s) (PMID: 30974434; 30426266; 29364747; 28976000; 28813618; 27881089; 24700731; 22581971; 21279306; 20979233; 21484994) - PS4.The p.(Phe228Ile) was detected in trans with a pathogenic variant (PMID: 30426266; 28976000; 28813618; 24700731; 22581971; 21279306; 20979233; 21484994) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 30426266; 24700731; 21279306; 20979233; 21484994) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Uruaguay
Pathogenic (Oct 07, 2022)	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020) Method: clinical testing	Not provided Affected status: yes Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV003802766.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (4) PubMed: 29364747‚ 28105635‚ 22581971‚ 30426266 Comment: The WNT10A c.682T>A (p.Phe228Ile) missense variant results in the substitution of phenylalanine at amino acid position 228 with isoleucine. This variant is one of the … (more) The WNT10A c.682T>A (p.Phe228Ile) missense variant results in the substitution of phenylalanine at amino acid position 228 with isoleucine. This variant is one of the most commonly reported WNT10A variants associated with hypodontia and ectodermal dysplasia. Across a selection of the available literature, the c.682T>A variant has been reported in a homozygous state in 12 unrelated affected individuals, in a compound heterozygous state in 11, and in a heterozygous state in six (PMID: 22581971; PMID: 28105635). It has also been shown to co-segregate with the phenotype with reduced penetrance in multiple families (PMID: 30426266). The highest frequency of this allele in the Genome Aggregation Database is 0.03482 in the Ashkenazi Jewish population (version 2.2.1). In the total population, it is reported in a homozygous state in 42 individuals. This frequency is high but consistent with the reduced penetrance demonstrated for the variant and the prevalence and variable expressivity of the disease. A case-control study of over 2000 individuals found the c.682T>A variant conferred a 3.25-fold increased risk for isolated tooth agenesis (95% CI: 2.74-3.85) (PMID: 29364747). This variant is located in the Wnt domain, in a region implicated in interactions with Frizzled and thus intracellular Wnt signaling (PMID: 28105635), and is predicted to affect protein function by computational algorithms. Based on the available evidence, the c.682T>A (p.Phe228Ile) variant is classified as pathogenic for WNT10A-related disorders. (less)
Pathogenic (Apr 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Odonto-onycho-dermal dysplasia Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV003927222.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (4) PubMed: 22581971‚ 28105635‚ 29364747‚ 35537890
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Ectodermal dysplasia Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004123096.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic, low penetrance (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tooth agenesis, selective, 4 Odonto-onycho-dermal dysplasia Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000638469.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 19559398‚ 28976000‚ 30974434‚ 29364747 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 228 of the WNT10A protein (p.Phe228Ile). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 228 of the WNT10A protein (p.Phe228Ile). This variant is present in population databases (rs121908120, gnomAD 3%), including at least one homozygous and/or hemizygous individual. This variant has been observed in many individuals with autosomal recessive forms of ectodermal dysplasia (PMID: 19559398, 28976000, 30974434, Invitae). It has been found in trans (on the opposite chromosome) from many different pathogenic variants. Based on an internal analysis, this variant is associated with reduced penetrance for autosomal recessive disease (15% when in homozygosity and 30-60% when present with another pathogenic variant) compared to other pathogenic or likely pathogenic variants, which have a penetrance of 70-80% (Invitae). In addition, in a large meta-analysis, this variant conferred a 2.25-3.42-fold increased risk (95% CI: 1.39-4.10) for isolated tooth agenesis, the autosomal dominant condition associated with WNT10A (PMID: 29364747). ClinVar contains an entry for this variant (Variation ID: 4462). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WNT10A protein function with a positive predictive value of 80%. In summary, this variant is reported to cause disease. However, because this variant is associated with a lower penetrance form of disease than other pathogenic alleles in the WNT10A gene, and because it is found in homozygosity in healthy individuals, it has been classified as Pathogenic (low penetrance). (less)
Pathogenic (Apr 25, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000741335.6 First in ClinVar: Apr 15, 2018 Last updated: Aug 11, 2024	Publications: PubMed (11) PubMed: 19559398‚ 22581971‚ 23401279‚ 24700731‚ 26964878‚ 27881089‚ 28813618‚ 28976000‚ 29364747‚ 29431110‚ 30426266 Comment: The c.682T>A (p.F228I) alteration is located in coding exon 3 of the WNT10A gene. This alteration results from a T to A substitution at nucleotide … (more) The c.682T>A (p.F228I) alteration is located in coding exon 3 of the WNT10A gene. This alteration results from a T to A substitution at nucleotide position 682, causing the phenylalanine (F) at amino acid position 228 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 1.372% (3770/274884) total alleles studied. The highest observed frequency was 3.482% (359/10310) of Ashkenazi Jewish alleles. The p.F228I alteration is often associated with a severe ectodermal dysplasia phenotype when occurring in the homozygous or compound heterozygous state with other pathogenic alterations (Bohring, 2009; Plaisancié, 2013; Reuter, 2018; Guazzarotti, 2018; Ruiz-Heiland, 2019). A genome-wide association study (GWAS) found a significant association between this alteration and tooth agenesis (p-value=5.2 x 10-6; odds ratio for heteterozygotes = 3.0; odds ratio for homozygotes = 51.3; Jonsson, 2018). Individuals who are heterozygous for the p.F228I alteration may have a mild phenotype including dental anomalies and palmar/plantar hyperkeratosis, though penetrance is incomplete and expression is variable (Bohring, 2009; Guazzarotti, 2018; Ruiz-Heiland, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248938.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: WNT10A: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3 Number of individuals with the variant: 12
Pathogenic (Oct 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tooth agenesis, selective, 4 Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399295.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (5) PubMed: 19559398‚ 28813618‚ 30046887‚ 30426266‚ 34228861 Comment: Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with odontoonychodermal dysplasia (MIM#257980), Schopf-Schulz-Passarge syndrome (MIM#224750) and selective tooth agenesis 4 (MIM#150400). (I) 0108 - This gene is associated with both recessive and dominant disease. Milder phenotypes are associated with dominant inheritance (OMIM, PMIDs: 19559398, 30426266). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMIDs: 19559398, 30426266). (I) 0115 - Variants in this gene are known to have variable expressivity. The same variants have been associated with all three OMIM phenotypes, with both dominant and recessive inheritance, and there is a high degree of variability of phenotypic expression (OMIM, PMIDs: 19559398, 30426266). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0306 - Variant is present in gnomAD (v4) >=0.03 and <0.05 for a recessive condition (32529 heterozygotes, 449 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Wnt domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple unrelated homozygous, compound heterozygous and heterozygous individuals with WNT10A-related ectodermal dysplasia, oligodontia and tooth agenesis (ClinVar, PMIDs: 19559398, 30426266, 30046887, 28813618, 34228861). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Feb 01, 2014)	no assertion criteria provided Method: literature only	ODONTOONYCHODERMAL DYSPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024892.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2017	Publications: PubMed (5) PubMed: 19559398‚ 21484994‚ 22581971‚ 23401279‚ 24449199 Comment on evidence: In 2 probands with odontoonychodermal dysplasia (OODD; 257980), Bohring et al. (2009) identified homozygosity for a 682T-A transversion in the WNT10A gene, resulting in a … (more) In 2 probands with odontoonychodermal dysplasia (OODD; 257980), Bohring et al. (2009) identified homozygosity for a 682T-A transversion in the WNT10A gene, resulting in a phe228-to-ile (F228I) substitution at an evolutionarily conserved residue. In 2 additional probands with OODD, the F228I mutation was found in compound heterozygosity with the C107X mutation (606268.0002). The F228I mutation was not found in 200 control chromosomes. Of 15 heterozygous carriers of the F228I mutation, 7 exhibited some phenotypic manifestation, including anomalies of teeth, skin, hair, and nails. In the affected father and eldest son from an American family with variable hypodontia involving lateral incisors and premolar teeth (STHAG4; 150400), Kantaputra and Sripathomsawat (2011) identified heterozygosity for the F228I mutation in the WNT10A gene. Another affected son, who had only microdontia of the left mandibular second premolar, was compound heterozygous for F228I and a 649G-A transition in exon 3 of the WNT10A gene, resulting in an asp217-to-asn (D217N; 606268.0007) substitution, which he had inherited from his unaffected mother, who had normal dentition. The D217N mutation was also present in heterozygosity in another affected son, who had absence of the maxillary permanent lateral incisors, mandibular second premolars, and a mandibular permanent lateral incisor. Examination of the family members revealed no other manifestations of ectodermal dysplasia. Neither mutation was found in 200 control chromosomes from individuals with normal dentition from a Thai DNA bank registry or in 400 Swedish and 400 Pakistani control chromosomes. In 13 patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) identified the F228I mutation in the WNT10A gene; the mutation was homozygous in 7 patients, heterozygous in 2 patients, and compound heterozygous with C107X in 3 patients and with G95K (606268.0008) in 1 patient. The authors noted that F228I was found in unselected controls at an allele frequency of 2.3%, reflecting the high prevalence of tooth agenesis in the general population. In addition, van den Boogaard et al. (2012) identified heterozygosity, homozygosity, or compound heterozygosity for the F228I mutation in 8 patients with tooth agenesis who had mild features of ectodermal dysplasia, but did not exhibit the characteristic features of OODD; 2 were heterozygous, 2 were homozygous, 3 were compound heterozygous for C207X and F228I, and 1 was compound heterozygous for C208X and a W277C mutation in WNT10A. In 8 probands with tooth agenesis, 7 of whom also exhibited features of ectodermal dysplasia, Plaisancie et al. (2013) identified the F228I mutation in the WNT10A gene, present in heterozygosity in 2 patients, in homozygosity in 3 patients, and in compound heterozygosity with another WNT10A variant in 3 patients. Of the 3 patients homozygous for F228I, 1 had severe tooth agenesis without other associated features, whereas the other 2 probands had tooth agenesis, conical teeth, and thin nails, as well as short stature in 1 of them and thick hair in the other. In a population-based study of 102 Swedish individuals with nonsyndromic tooth agenesis, Arzoo et al. (2014) identified the F228I variant in the WNT10A gene as the most prevalent variant in their cohort. It represented 13.3% of all oligodontia alleles and was found in 21 of 94 probands. (less)
Pathogenic (Feb 01, 2014)	no assertion criteria provided Method: literature only	TOOTH AGENESIS, SELECTIVE, 4, WITH OR WITHOUT ECTODERMAL DYSPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000536682.1 First in ClinVar: Mar 12, 2017 Last updated: Mar 12, 2017	Publications: PubMed (5) PubMed: 19559398‚ 21484994‚ 22581971‚ 23401279‚ 24449199 Comment on evidence: In 2 probands with odontoonychodermal dysplasia (OODD; 257980), Bohring et al. (2009) identified homozygosity for a 682T-A transversion in the WNT10A gene, resulting in a … (more) In 2 probands with odontoonychodermal dysplasia (OODD; 257980), Bohring et al. (2009) identified homozygosity for a 682T-A transversion in the WNT10A gene, resulting in a phe228-to-ile (F228I) substitution at an evolutionarily conserved residue. In 2 additional probands with OODD, the F228I mutation was found in compound heterozygosity with the C107X mutation (606268.0002). The F228I mutation was not found in 200 control chromosomes. Of 15 heterozygous carriers of the F228I mutation, 7 exhibited some phenotypic manifestation, including anomalies of teeth, skin, hair, and nails. In the affected father and eldest son from an American family with variable hypodontia involving lateral incisors and premolar teeth (STHAG4; 150400), Kantaputra and Sripathomsawat (2011) identified heterozygosity for the F228I mutation in the WNT10A gene. Another affected son, who had only microdontia of the left mandibular second premolar, was compound heterozygous for F228I and a 649G-A transition in exon 3 of the WNT10A gene, resulting in an asp217-to-asn (D217N; 606268.0007) substitution, which he had inherited from his unaffected mother, who had normal dentition. The D217N mutation was also present in heterozygosity in another affected son, who had absence of the maxillary permanent lateral incisors, mandibular second premolars, and a mandibular permanent lateral incisor. Examination of the family members revealed no other manifestations of ectodermal dysplasia. Neither mutation was found in 200 control chromosomes from individuals with normal dentition from a Thai DNA bank registry or in 400 Swedish and 400 Pakistani control chromosomes. In 13 patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) identified the F228I mutation in the WNT10A gene; the mutation was homozygous in 7 patients, heterozygous in 2 patients, and compound heterozygous with C107X in 3 patients and with G95K (606268.0008) in 1 patient. The authors noted that F228I was found in unselected controls at an allele frequency of 2.3%, reflecting the high prevalence of tooth agenesis in the general population. In addition, van den Boogaard et al. (2012) identified heterozygosity, homozygosity, or compound heterozygosity for the F228I mutation in 8 patients with tooth agenesis who had mild features of ectodermal dysplasia, but did not exhibit the characteristic features of OODD; 2 were heterozygous, 2 were homozygous, 3 were compound heterozygous for C207X and F228I, and 1 was compound heterozygous for C208X and a W277C mutation in WNT10A. In 8 probands with tooth agenesis, 7 of whom also exhibited features of ectodermal dysplasia, Plaisancie et al. (2013) identified the F228I mutation in the WNT10A gene, present in heterozygosity in 2 patients, in homozygosity in 3 patients, and in compound heterozygosity with another WNT10A variant in 3 patients. Of the 3 patients homozygous for F228I, 1 had severe tooth agenesis without other associated features, whereas the other 2 probands had tooth agenesis, conical teeth, and thin nails, as well as short stature in 1 of them and thick hair in the other. In a population-based study of 102 Swedish individuals with nonsyndromic tooth agenesis, Arzoo et al. (2014) identified the F228I variant in the WNT10A gene as the most prevalent variant in their cohort. It represented 13.3% of all oligodontia alleles and was found in 21 of 94 probands. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968123.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Apr 15, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: paternal	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031389.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Selective tooth agenesis (present)
Pathogenic (Aug 23, 2024)	no assertion criteria provided Method: clinical testing	WNT10A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004106117.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The WNT10A c.682T>A variant is predicted to result in the amino acid substitution p.Phe228Ile. This variant has been reported in the heterozygous and compound heterozygous … (more) The WNT10A c.682T>A variant is predicted to result in the amino acid substitution p.Phe228Ile. This variant has been reported in the heterozygous and compound heterozygous states as the most common variant found in patients affected with taurodontism, non-syndromic missing teeth, or mild ectodermal dysplasia (Vink et al. 2014. PubMed ID: 24398796; Yang et al. 2015. PubMed ID: 25629078; Arzoo et al. 2014. PubMed ID: 24449199; Bergendal et al. 2016. PubMed ID: 27881089; Guazzarotti et al. 2018. PubMed ID: 28976000). However, this variant was also observed in a genomic variant database with minor allele frequencies ranging from 0% to ~3.5%, with >40 homozygotes listed. Incomplete penetrance has been documented for this variant (Yang et al. 2015. PubMed ID: 25629078). Based on this evidence, this variant is interpreted as pathogenic. (less)
Pathogenic (Sep 15, 2014)	no assertion criteria provided Method: literature only	Tooth agenesis Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Accession: SCV000987049.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Publications: PubMed (1) PubMed: 25629078
not provided (-)	no classification provided Method: literature only	Ectodermal dysplasia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001977603.2 First in ClinVar: Oct 16, 2021 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1112 BookShelf: NBK1112
not provided (-)	no classification provided Method: phenotyping only	Odonto-onycho-dermal dysplasia SchC6pf-Schulz-Passarge syndrome Tooth agenesis, selective, 4 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: paternal	GenomeConnect - Brain Gene Registry Accession: SCV003931259.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: Variant classified as Pathogenic and reported on 02-18-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does … (more) Variant classified as Pathogenic and reported on 02-18-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Failure to thrive (present) , Abnormality of eye movement (present) , Myopia (present) , Ptosis (present) , Ear malformation (present) , Cognitive impairment (present) , … (more) Failure to thrive (present) , Abnormality of eye movement (present) , Myopia (present) , Ptosis (present) , Ear malformation (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2020-02-18 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Odonto-onycho-dermal dysplasia SchC6pf-Schulz-Passarge syndrome Tooth agenesis, selective, 4 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749715.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant interpreted as Pathogenic and reported on 01-00-1900 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpreted as Pathogenic and reported on 01-00-1900 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormal oral cavity morphology (present) , Hyperpigmentation of the skin (present) , Thickened skin (present) , Asthma (present) , Recurrent infections (present) , Abnormal intestine … (more) Abnormal oral cavity morphology (present) , Hyperpigmentation of the skin (present) , Thickened skin (present) , Asthma (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Anxiety (present) , Abnormal delivery (present) (less) Indication for testing: Diagnostic, Family Testing Age: 30-39 years Sex: female Testing laboratory: Invitae Testing laboratory interpretation: Pathogenic
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Comment:

The WNT10A c.682T>A variant is classified as LIKELY PATHOGENIC (low penetrance) (PP3, PS3, PS4) The WNT10A c.682T>A variant is a single nucleotide change in exon 3 of the WNT10A gene, which is predicted to change the amino acid phenylalanine at position 228 in the protein to isoleucine. This variant has been reported in a heterozygous state in many individuals with isolated hypodontia or oligodontia, as well as in unaffected carriers and is therefore considered to be a pathogenic variant with low penetrance. Although the population frequency is high (approximately 1.37%), the incidence of this dental agenesis is significantly higher (approximately 6.75%) (PMID:25713620) (PS4). Large meta analysis shows 2.25 - 3.42 fold increased risk for isolated tooth agenesis (PMID:29364747) (PS3). This variant has conflicting reports of pathogenicity in ClinVar, although the majority of other diagnostic laboratories classify it as pathogenic (ClinVar Variation ID: 19501). This variant has been reported as damaging in HGMD (CM094237). Computational predictions support a deleterious effect on the gene or gene product (PP3).

Comment:

The p.Phe228Ile variant in WNT10A has been reported in over 50 individuals with clinical features of ectodermal dysplasia or isolated tooth agenesis (hypodontia) in the homozygous or compound heterozygous state. It has also been seen in the heterozygous state in individuals with tooth agenesis with or without some features of ectodermal dysplasia as well as in asymptomatic family members. This variant segregated with disease in at least 17 affected individuals from multiple families (Bohring 2009 PMID: 19559398, Kantaputra 2011 PMID: 21484994, van den Boogaard 2012 PMID: 22581971, Mostowska 2013 PMID: 23167694, Plaisancie 2013 PMID: 23401279, Arzoo 2013 PMID: 24449199, Mues 2014 PMID: 24700731). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 4462) and has been identified in 3.5% (120/3470) of Ashkenazi Jewish and 2.2% (1515/67998) of European chromosomes, including many homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). However, studies have consistently found that it is in a significantly higher proportion of tooth agenesis cohorts than control cohorts (Bohring 2009 PMID: 19559398, Arzoo 2013 PMID: 24449199, Mues 2014 PMID: 24700731). In a large meta-analysis, this variant was associated with a 2.25-3.42-fold risk (95% CI: 1.39-4.10) for isolated tooth agenesis, the autosomal dominant condition associated with WNT10A (Jonsson 2018 PMID: 29364747). This variant is thought to have lower penetrance with variable expressivity, as heterozygotes for this variant were either asymptomatic or had hypodontia and/or mild clinical features of ectodermal dysplasia (Bohring 2009 PMID: 19559398). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for clinical features of ectodermal dysplasia, ranging from isolated tooth agenesis with or without other clinical features in the heterozygous state to a classic ectodermal dysplasia phenotype in the homozygous or compound heterozygous state. However, this variant is associated with a lower penetrant disease compared to other pathogenic variants in the WNT10A gene. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PP3.

Comment:

This variant has been identified in an individual with congenital alopecia, hypodontia, and hypohidrosis. In the family, inheritance was compatible with a dominant pattern. This nonsynonymous variant is reported with an estimated allele frequency of 0.014 in gnomAD exomes, 0.01215 in gnomAD genomes, and 0.019 in NHLI Exome Sequencing Project (ESP). The nucleotide position is conserved across 35 mammalian species (GERP RS: 4.46). In silico analysis indicates that the variant might be damaging (MutationTaster: disease-causing; FATHMM-MKL: damaging; Provean: damaging; DANN: 0.992). The p.Phe228Ile mutation represents the most common allele identified in cases with isolated hypodontia (PMIDs: 22581971, 24449199, 24700731). Reduced penetrance and variable expressivity have been reported in carriers of the p.Phe228Ile mutation. Nearly half of heterozygotes may display mild multifocal symptoms, such as variable abnormalities of skin, hair, teeth or nails (PMIDs: 19559398, 21279306). For instance, van den Boogaard et al. (PMID: 22581971) reported a p.Phe228Ile heterozygote presenting with hypodontia, alopecia, hypohidrosis and mild nail dysplasia. Autosomal dominant inheritance of isolated hypodontia-microdontia in p.Phe228Ile heterozygotes has been described also by Kantaputra and Sripathomsawat (PMID: 21484994).

Comment:

One of the most common pathogenic variants reported in this gene associated with semi-dominant ectodermal dysplasia with variable expressivity; Observed in the heterozygous state in individuals with isolated hypodontia or oligodontia, in individuals with other features of ectodermal dysplasia, and also in unaffected carriers (Bohring et al., 2009; Kantaputra et al., 2011; Cluzeau et al., 2011; van den Boogaard et al., 2012; Mostowska et al., 2013; Plaisancie et al., 2013; Tardieu et al., 2017); Case control studies suggest this variant is associated with hypodontia (van den Boogaard et al., 2012); 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: 21484994, 20301291, 23401279, 22581971, 24700731, 23167694, 24398796, 24123366, 25333069, 21228398, 24702986, 23991204, 25629078, 19559398, 28105635, 20979233, 27881089, 26049155, 25545742, 26087098, 28813618, 28976000, 29364747, 29364501, 29431110, 24449199, 21279306, 30046887, 30426266, 31798653, 32618450, 31618753, 33144682)

Comment:

The c.682T>A;p.(Phe228Ile) missense variant has been observed in affected individual(s) (PMID: 30974434; 30426266; 29364747; 28976000; 28813618; 27881089; 24700731; 22581971; 21279306; 20979233; 21484994) - PS4.The p.(Phe228Ile) was detected in trans with a pathogenic variant (PMID: 30426266; 28976000; 28813618; 24700731; 22581971; 21279306; 20979233; 21484994) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 30426266; 24700731; 21279306; 20979233; 21484994) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The WNT10A c.682T>A (p.Phe228Ile) missense variant results in the substitution of phenylalanine at amino acid position 228 with isoleucine. This variant is one of the most commonly reported WNT10A variants associated with hypodontia and ectodermal dysplasia. Across a selection of the available literature, the c.682T>A variant has been reported in a homozygous state in 12 unrelated affected individuals, in a compound heterozygous state in 11, and in a heterozygous state in six (PMID: 22581971; PMID: 28105635). It has also been shown to co-segregate with the phenotype with reduced penetrance in multiple families (PMID: 30426266). The highest frequency of this allele in the Genome Aggregation Database is 0.03482 in the Ashkenazi Jewish population (version 2.2.1). In the total population, it is reported in a homozygous state in 42 individuals. This frequency is high but consistent with the reduced penetrance demonstrated for the variant and the prevalence and variable expressivity of the disease. A case-control study of over 2000 individuals found the c.682T>A variant conferred a 3.25-fold increased risk for isolated tooth agenesis (95% CI: 2.74-3.85) (PMID: 29364747). This variant is located in the Wnt domain, in a region implicated in interactions with Frizzled and thus intracellular Wnt signaling (PMID: 28105635), and is predicted to affect protein function by computational algorithms. Based on the available evidence, the c.682T>A (p.Phe228Ile) variant is classified as pathogenic for WNT10A-related disorders.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 228 of the WNT10A protein (p.Phe228Ile). This variant is present in population databases (rs121908120, gnomAD 3%), including at least one homozygous and/or hemizygous individual. This variant has been observed in many individuals with autosomal recessive forms of ectodermal dysplasia (PMID: 19559398, 28976000, 30974434, Invitae). It has been found in trans (on the opposite chromosome) from many different pathogenic variants. Based on an internal analysis, this variant is associated with reduced penetrance for autosomal recessive disease (15% when in homozygosity and 30-60% when present with another pathogenic variant) compared to other pathogenic or likely pathogenic variants, which have a penetrance of 70-80% (Invitae). In addition, in a large meta-analysis, this variant conferred a 2.25-3.42-fold increased risk (95% CI: 1.39-4.10) for isolated tooth agenesis, the autosomal dominant condition associated with WNT10A (PMID: 29364747). ClinVar contains an entry for this variant (Variation ID: 4462). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WNT10A protein function with a positive predictive value of 80%. In summary, this variant is reported to cause disease. However, because this variant is associated with a lower penetrance form of disease than other pathogenic alleles in the WNT10A gene, and because it is found in homozygosity in healthy individuals, it has been classified as Pathogenic (low penetrance).

Comment:

The c.682T>A (p.F228I) alteration is located in coding exon 3 of the WNT10A gene. This alteration results from a T to A substitution at nucleotide position 682, causing the phenylalanine (F) at amino acid position 228 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 1.372% (3770/274884) total alleles studied. The highest observed frequency was 3.482% (359/10310) of Ashkenazi Jewish alleles. The p.F228I alteration is often associated with a severe ectodermal dysplasia phenotype when occurring in the homozygous or compound heterozygous state with other pathogenic alterations (Bohring, 2009; Plaisancié, 2013; Reuter, 2018; Guazzarotti, 2018; Ruiz-Heiland, 2019). A genome-wide association study (GWAS) found a significant association between this alteration and tooth agenesis (p-value=5.2 x 10-6; odds ratio for heteterozygotes = 3.0; odds ratio for homozygotes = 51.3; Jonsson, 2018). Individuals who are heterozygous for the p.F228I alteration may have a mild phenotype including dental anomalies and palmar/plantar hyperkeratosis, though penetrance is incomplete and expression is variable (Bohring, 2009; Guazzarotti, 2018; Ruiz-Heiland, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with odontoonychodermal dysplasia (MIM#257980), Schopf-Schulz-Passarge syndrome (MIM#224750) and selective tooth agenesis 4 (MIM#150400). (I) 0108 - This gene is associated with both recessive and dominant disease. Milder phenotypes are associated with dominant inheritance (OMIM, PMIDs: 19559398, 30426266). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMIDs: 19559398, 30426266). (I) 0115 - Variants in this gene are known to have variable expressivity. The same variants have been associated with all three OMIM phenotypes, with both dominant and recessive inheritance, and there is a high degree of variability of phenotypic expression (OMIM, PMIDs: 19559398, 30426266). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0306 - Variant is present in gnomAD (v4) >=0.03 and <0.05 for a recessive condition (32529 heterozygotes, 449 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Wnt domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple unrelated homozygous, compound heterozygous and heterozygous individuals with WNT10A-related ectodermal dysplasia, oligodontia and tooth agenesis (ClinVar, PMIDs: 19559398, 30426266, 30046887, 28813618, 34228861). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The WNT10A c.682T>A variant is predicted to result in the amino acid substitution p.Phe228Ile. This variant has been reported in the heterozygous and compound heterozygous states as the most common variant found in patients affected with taurodontism, non-syndromic missing teeth, or mild ectodermal dysplasia (Vink et al. 2014. PubMed ID: 24398796; Yang et al. 2015. PubMed ID: 25629078; Arzoo et al. 2014. PubMed ID: 24449199; Bergendal et al. 2016. PubMed ID: 27881089; Guazzarotti et al. 2018. PubMed ID: 28976000). However, this variant was also observed in a genomic variant database with minor allele frequencies ranging from 0% to ~3.5%, with >40 homozygotes listed. Incomplete penetrance has been documented for this variant (Yang et al. 2015. PubMed ID: 25629078). Based on this evidence, this variant is interpreted as pathogenic.

Comment:

Variant classified as Pathogenic and reported on 02-18-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Comment:

Variant interpreted as Pathogenic and reported on 01-00-1900 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel Dental Anomaly-associated Mutations in WNT10A Protein Binding Sites.	Kantaputra P	International dental journal	2023	PMID: 35537890
Gastrointestinal symptoms in patients with isolated oligodontia and a Wnt gene mutation.	Ross JN	Oral diseases	2023	PMID: 34228861
Hypohidrotic Ectodermal Dysplasia.	Adam MP	-	2022	PMID: 20301291
Turkish Ectodermal Dysplasia Cohort: From Phenotype to Genotype in 17 Families.	Güven Y	Cytogenetic and genome research	2019	PMID: 30974434
Prevalence of WNT10A gene mutations in non-syndromic oligodontia.	Ruiz-Heiland G	Clinical oral investigations	2019	PMID: 30426266
Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.	Du R	Human genetics	2018	PMID: 30046887
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.	Reuter MS	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2018	PMID: 29431110
Rare and Common Variants Conferring Risk of Tooth Agenesis.	Jonsson L	Journal of dental research	2018	PMID: 29364747
WNT10A gene is the second molecular candidate in a cohort of young Italian subjects with ectodermal derivative impairment (EDI).	Guazzarotti L	Clinical genetics	2018	PMID: 28976000
Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.	Dinckan N	Journal of dental research	2018	PMID: 28813618
Dental and extra-oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype-phenotype study.	Tardieu C	Clinical genetics	2017	PMID: 28105635
Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency.	Bergendal B	BMC medical genetics	2016	PMID: 27881089
Odonto-onycho-dermal dysplasia in a patient homozygous for a WNT10A nonsense mutation and mild manifestations of ectodermal dysplasia in carriers of the mutation.	Krøigård AB	BMC dermatology	2016	PMID: 26964878
Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds.	Yang J	Molecular genetics & genomic medicine	2015	PMID: 25629078
A study of prevalence and distribution of tooth agenesis.	Bozga A	Journal of medicine and life	2014	PMID: 25713620
The WNT10A gene in ectodermal dysplasias and selective tooth agenesis.	Mues G	American journal of medical genetics. Part A	2014	PMID: 24700731
WNT10A mutations account for ¼ of population-based isolated oligodontia and show phenotypic correlations.	Arzoo PS	American journal of medical genetics. Part A	2014	PMID: 24449199
Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia.	Plaisancié J	American journal of medical genetics. Part A	2013	PMID: 23401279
Nucleotide variants of genes encoding components of the Wnt signalling pathway and the risk of non-syndromic tooth agenesis.	Mostowska A	Clinical genetics	2013	PMID: 23167694
Mutations in WNT10A are present in more than half of isolated hypodontia cases.	van den Boogaard MJ	Journal of medical genetics	2012	PMID: 22581971
WNT10A and isolated hypodontia.	Kantaputra P	American journal of medical genetics. Part A	2011	PMID: 21484994
Intra-familial variability of ectodermal defects associated with WNT10A mutations.	Wedgeworth EK	Acta dermato-venereologica	2011	PMID: 21279306
Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.	Cluzeau C	Human mutation	2011	PMID: 20979233
WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes.	Bohring A	American journal of human genetics	2009	PMID: 19559398
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Text-mined citations for rs121908120 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_025216.3(WNT10A):c.682T>A (p.Phe228Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908120 ...