Submissions for variant NM_006147.4(IRF6):c.250C>T (p.Arg84Cys)

dbSNP: rs121434226

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255145	SCV000321780	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.(R84C) interferes with the DNA-binding ability of the IRF6 protein (Little et al., 2009; Kondo et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18617879, 23406900, 15472655, 25547932, 22488974, 25548624, 26346622, 25489771, 12219090, 28945736, 28795449, 23154410, 31488442, 19036739, 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002227986	SCV000832675	pathogenic	Orofacial cleft 6, susceptibility to; Popliteal pterygium syndrome; Van der Woude syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 84 of the IRF6 protein (p.Arg84Cys). This missense change has been observed in individual(s) with popliteal pterygium syndrome (PMID: 18617879, 22488974, 25547932, 25548624). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IRF6 function (PMID: 19036739). 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 IRF6 protein function. ClinVar contains an entry for this variant (Variation ID: 3414).
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001775062	SCV004543839	pathogenic	Autosomal dominant popliteal pterygium syndrome	2023-05-26	criteria provided, single submitter	clinical testing
OMIM	RCV000003583	SCV000023741	pathogenic	Popliteal pterygium syndrome	2002-10-01	no assertion criteria provided	literature only
GeneReviews	RCV001775062	SCV002012474	not provided	Autosomal dominant popliteal pterygium syndrome		no assertion provided	literature only	Most commonly seen in persons with popliteal pterygium syndrome
PreventionGenetics, part of Exact Sciences	RCV004554583	SCV004117344	pathogenic	IRF6-related condition	2024-04-05	no assertion criteria provided	clinical testing	The IRF6 c.250C>T variant is predicted to result in the amino acid substitution p.Arg84Cys. This variant has been reported to be pathogenic for IRF6-related disorders (Kosaki et al. 2012. PubMed ID: 22488974; Leslie et al. 2016. PubMed ID: 26346622; Ratbi et al. 2014. PubMed ID: 25547932; Mubungu et al. 2014. PubMed ID: 25548624). In addition, different missense variants impacting the same amino acid (p.Arg84His, p.Arg84Gly, p.Arg84Pro, and p.Arg84Leu) have also been documented to be pathogenic for IRF6-related disorders (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). The c.250C>T (p.Arg84Cys) variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.