Submissions for variant NM_030632.3(ASXL3):c.4462_4465del (p.Thr1488fs)

dbSNP: rs1599574018

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008841	SCV001168645	pathogenic	not provided	2018-06-27	criteria provided, single submitter	clinical testing	A pathogenic variant has been identified in the ASXL3 gene. The c.4462_4465delACTG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.4462_4465delACTG variant causes a frameshift starting with codon Threonine 1488, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Thr1488SerfsX17. This frameshift variant is predicted to result in protein truncation, as the last 761 amino acids are lost and replaced with 16 incorrect amino acids. The c.4462_4465delACTG variant is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of c.4462_4465delACTG is consistent with the diagnosis of Bainbridge-Ropers syndrome in this individual.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001264798	SCV001442995	uncertain significance	Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	2020-11-16	criteria provided, single submitter	clinical testing	This variant was identified in heterozygous state in two siblings with mild ID, microcephaly, aggressive behavior and self-mutilation. The unaffected father carries the variant as well in heterozygous state. It results in a frameshift in last exon, other disease causing variant downstream is published (June 2020, PMID: 32240826) or were submitted to DECIPHER. PVS1_Strong, PM2, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001008841	SCV001578904	pathogenic	not provided	2020-04-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Bainbridge-Ropers Syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 817642). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ASXL3 gene (p.Thr1488Serfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 761 amino acids of the ASXL3 protein.
GenomeConnect - Simons Searchlight	RCV001264798	SCV001443338	pathogenic	Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	2018-04-20	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-20 and interpreted as Pathogenic. Variant was initially reported on 2017-03-02 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.
GenomeConnect - Brain Gene Registry	RCV001264798	SCV004804619	not provided	Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 07-11-2021 by GeneDx. 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/.