Submissions for variant NM_005249.5(FOXG1):c.759C>A (p.Asn253Lys)

dbSNP: rs767873754

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV001171512	SCV001245456	likely pathogenic	Rett syndrome, congenital variant	2020-04-20	criteria provided, single submitter	clinical testing	The variant c.759C> A; p.(Asn253Lys) in the FOXG1 gene (transcript: NM_005249.4) is not listed in population-related databases (gnomAD, 1OOOGenomes and Exome Variant Server). It is also not listed in the phenotype-related databases HGMD, ClinVar and LOVD. However, the variant c.757A> G; p.(Asn253Asp), which affects the same amino acid, has already been described as pathogenic (see PMID: 21441262). The mutation prediction programs MutationTaster, Polyphen, SIFT and PROVEAN rate the variant as pathogenic, the CADD score is 27.6. The in silica analysis using the Alamut software does not provide any clear indication of a change in splicing behavior with various prediction programs, only the Human Splicing Finder program predicts the generation of a new donor splicing site. The FOXG1 variant was also detected in the patient's brother, who was also affected. The mother was found in one of 132 reads of the sequencing data. Overall, the FOXG1 variant is probably considered pathogenic (PM1, PM2, PM5, PP2, PP3).