Submissions for variant NM_001349338.3(FOXP1):c.1438G>A (p.Glu480Lys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003416911	SCV004108326	likely pathogenic	FOXP1-related disorder	2023-05-24	criteria provided, single submitter	clinical testing	The FOXP1 c.1438G>A variant is predicted to result in the amino acid substitution p.Glu480Lys. This variant has been reported as de novo in a patient with a neurodevelopmental disorder (Han et al. 2019. PubMed ID: 31199603). 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003730579	SCV004535310	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 480 of the FOXP1 protein (p.Glu480Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and speech delay (PMID: 31199603). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FOXP1 protein function. Studies have shown that this missense change alters FOXP1 gene expression (PMID: 31199603).