Submissions for variant NM_025216.3(WNT10A):c.661G>A (p.Gly221Arg)

gnomAD frequency: 0.00001  dbSNP: rs775380022

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489933	SCV000577667	likely pathogenic	not provided	2022-12-02	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037834	SCV001201266	pathogenic	Odonto-onycho-dermal dysplasia; Tooth agenesis, selective, 4	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 221 of the WNT10A protein (p.Gly221Arg). This variant is present in population databases (rs775380022, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of WNT10A-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 427045). 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%. This variant disrupts the p.Gly221 amino acid residue in WNT10A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323568	SCV004029728	uncertain significance	not specified	2023-07-13	criteria provided, single submitter	clinical testing	Variant summary: WNT10A c.661G>A (p.Gly221Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246590 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.661G>A in individuals affected with Odonto-onycho-dermal dysplasia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004541539	SCV004787124	uncertain significance	WNT10A-related disorder	2024-02-29	no assertion criteria provided	clinical testing	The WNT10A c.661G>A variant is predicted to result in the amino acid substitution p.Gly221Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.