Submissions for variant NM_001904.4(CTNNB1):c.1723G>A (p.Gly575Arg)

dbSNP: rs797044875

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190686	SCV000244126	likely pathogenic	Inborn genetic diseases	2014-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852533	SCV002239738	pathogenic	not provided	2021-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 575 of the CTNNB1 protein (p.Gly575Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with CTNNB1-related conditions (PMID: 33350591). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208674). 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 CTNNB1 protein function. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470806	SCV002769145	likely pathogenic	Severe intellectual disability-progressive spastic diplegia syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with exudative vitreoretinopathy 7 (EVR; MIM#617572) and neurodevelopmental disorder with spastic diplegia and visual defects (MIM#615075). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported de novo in least two individuals described to have autism spectrum disorder and neurodevelopmental disorder, respectively (PMID: 28330790, 33350591). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002470806	SCV005061855	likely pathogenic	Severe intellectual disability-progressive spastic diplegia syndrome	2024-06-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001852533	SCV005414766	pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 28330790, 26795593, 33350591, 34582765, 36083290, 36790797)
Daryl Scott Lab, Baylor College of Medicine	RCV004745260	SCV005871024	likely pathogenic	CTNNB1-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PS2, PM2, PP3
PreventionGenetics, part of Exact Sciences	RCV004745260	SCV005343176	pathogenic	CTNNB1-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The CTNNB1 c.1723G>A variant is predicted to result in the amino acid substitution p.Gly575Arg. This variant has been recurrently reported to occur de novo in individuals with familial exudative vitreoretinopathy (Patient 3, Table 1, Rossetti et al. 2021. PubMed ID: 33350591; Kayumi et al. 2022. PubMed ID: 36083290; Table 1, Huang et al. 2023. PubMed ID: 36790797). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.