Submissions for variant NM_005430.4(WNT1):c.506G>A (p.Gly169Asp)

gnomAD frequency: 0.00009  dbSNP: rs371672410

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001586557	SCV001813958	uncertain significance	not provided	2019-12-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33195954, 28725987, 27450065, 30715774, 29552441, 30913006)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001586557	SCV002231657	pathogenic	not provided	2024-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 169 of the WNT1 protein (p.Gly169Asp). This variant is present in population databases (rs371672410, gnomAD 0.09%). This missense change has been observed in individual(s) with autosomal recessive osteogenesis imperfecta (PMID: 27450065, 30715774, 30913006). 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: 1212910). 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 WNT1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002276822	SCV002500226	likely pathogenic	Osteogenesis imperfecta	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: WNT1 c.506G>A (p.Gly169Asp) 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 8.6e-05 in 232802 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WNT1 causing Osteogenesis Imperfecta (8.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.506G>A has been reported in the literature in the compound heterozygous state in individuals affected with Osteogenesis Imperfecta (e.g. Liu_2016, Cao_2019, Li_2019, Hu_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30913006, 36595228, 30715774, 27450065, 28725987, 36056132, 33195954). ClinVar contains an entry for this variant (Variation ID: 1212910). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276822	SCV002565066	uncertain significance	Osteogenesis imperfecta	2020-05-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002569120	SCV003728608	uncertain significance	Inborn genetic diseases	2022-01-07	criteria provided, single submitter	clinical testing	The c.506G>A (p.G169D) alteration is located in exon 3 (coding exon 3) of the WNT1 gene. This alteration results from a G to A substitution at nucleotide position 506, causing the glycine (G) at amino acid position 169 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003416401	SCV004116953	uncertain significance	WNT1-related disorder	2022-10-16	criteria provided, single submitter	clinical testing	The WNT1 c.506G>A variant is predicted to result in the amino acid substitution p.Gly169Asp. This variant along with a second variant in WNT1 was reported in at least two individuals with osteogenesis imperfecta (Liu et al 2016. PubMed ID: 27450065; Table S1, Li L et al 2019. PubMed ID: 30715774; Cao et al 2019. PubMed ID: 30913006; Xi L et al 2021. PubMed ID: 34335676). This variant in the heterozygous condition along with two uncertain variants in PLS3 and NOTCH2 was reported in one individual with osteoporosis (reported as p.Gly169Asp, Rocha-Braz MGM et al 2020. PubMed ID: 33195954). In addition, a similar variant (p.Gly169Cys) was also reported to be associated with osteogenesis imperfecta (Liu. 2016. PubMed ID: 27450065; Zhang et al. 2021. PubMed ID: 34078411). This variant is reported in 0.097% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-49374354-G-A). In ClinVar, this variant was interpreted as uncertain and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1212910/?new_evidence=false). This variant could be pathogenic. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics	RCV005005975	SCV005634648	likely pathogenic	Osteogenesis imperfecta type 15; OSTEOPOROSIS, EARLY-ONSET, SUSCEPTIBILITY TO	2024-03-27	criteria provided, single submitter	clinical testing