Submissions for variant NM_001349338.3(FOXP1):c.1540C>T (p.Arg514Cys)

dbSNP: rs869025203

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Language and Genetics Department, Max Planck Institute for Psycholinguistics	RCV000207490	SCV000246200	pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2015-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267938	SCV001446455	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001267938	SCV002051538	pathogenic	not provided	2020-12-29	criteria provided, single submitter	clinical testing	PS3, PM2, PM6, PS4_Moderate
DASA	RCV000207490	SCV002061152	pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The c.1540C>T;p.(Arg514Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217265; PMID: 26647308) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (Forkhead domain) - PM1. This variant is not present in population databases (rs869025203, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 28741757 - c.1541G>A (p.Arg514His) - ) - .PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000207490	SCV002767206	pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with intellectual disability with language impairment and with or without autistic features (MIM#613670). Loss of function leading to haploinsufficiency has been demonstrated, however some variants have also been shown to bind to wild type FOXP1 and affect wild type function and localisation (PMID: 26647308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (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) 0601 - Variant is located in the well-established functional forkhead domain. Moreover, the affected residue is a DNA binding site (Decipher; NCBI conserved domain). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg514His) variant is de novo in three unrelated individuals with mild to severe intellectual disability (PMID: 28741757). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is de novo in two individuals with intellectual disability (ClinVar, PMID: 26647308). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into HEK293T cells resulted in reduced protein expression with subsequent mis-localisation and reduced transcriptional repression ability of the protein (PMID: 26647308). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001267938	SCV003194978	pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26647308, 31199603, 28741757, 34109629, 31981491)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001267938	SCV003525557	pathogenic	not provided	2024-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 514 of the FOXP1 protein (p.Arg514Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 26647308). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217265). 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 FOXP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg514 amino acid residue in FOXP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28741757). 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.
PreventionGenetics, part of Exact Sciences	RCV003417726	SCV004106266	pathogenic	FOXP1-related disorder	2023-01-06	criteria provided, single submitter	clinical testing	The FOXP1 c.1540C>T variant is predicted to result in the amino acid substitution p.Arg514Cys. This variant has been reported de novo in individuals with global developmental disorder, intellectual disability, and/or speech and language delay (Sollis et al. 2015. PubMed ID: 26647308; Braden et al. 2021. PubMed ID: 34109629). Function studies have shown that this variant impacts protein function (Sollis et al. 2015. PubMed ID: 26647308; Estruch et al. 2018. PMID: 29365100). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/217265/). This variant is interpreted as pathogenic.
OMIM	RCV004701260	SCV000502987	pathogenic	INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES	2024-10-16	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001267938	SCV001808292	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001267938	SCV001952578	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000207490	SCV004101077	likely pathogenic	Intellectual disability-severe speech delay-mild dysmorphism syndrome	2023-11-02	no assertion criteria provided	clinical testing