Submissions for variant NM_020988.3(GNAO1):c.143C>T (p.Thr48Ile)

dbSNP: rs1555499800

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000499510	SCV000595012	likely pathogenic	Developmental and epileptic encephalopathy, 17	2016-07-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524192	SCV003269011	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 GNAO1 protein function. ClinVar contains an entry for this variant (Variation ID: 435341). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 48 of the GNAO1 protein (p.Thr48Ile).
Ambry Genetics	RCV004023375	SCV004877039	pathogenic	Inborn genetic diseases	2024-03-14	criteria provided, single submitter	clinical testing	The c.143C>T (p.T48I) alteration is located in exon 2 (coding exon 2) of the GNAO1 gene. This alteration results from a C to T substitution at nucleotide position 143, causing the threonine (T) at amino acid position 48 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with epilepsy, movement disorders, seizures, and other clinical features consistent with GNAO1 encephalopathy (Domínguez-Carral, 2023; Li, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GenomeConnect - Brain Gene Registry	RCV003458445	SCV004176879	not provided	Developmental and epileptic encephalopathy, 17; Neurodevelopmental disorder with involuntary movements		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 05-09-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.