Submissions for variant NM_004586.3(RPS6KA3):c.2168G>A (p.Arg723His)

gnomAD frequency: 0.00133  dbSNP: rs144984628

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000595652	SCV000248737	likely benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000595652	SCV000706504	benign	not specified	2017-02-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317706	SCV000851928	benign	Inborn genetic diseases	2017-07-05	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000193624	SCV000883118	likely benign	Intellectual disability, X-linked 19	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000990499	SCV001141503	benign	Coffin-Lowry syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV001517241	SCV001725711	benign	Coffin-Lowry syndrome; Intellectual disability, X-linked 19	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001610515	SCV001834480	benign	not provided	2019-06-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31019283, 30378261, 16879200, 11180593)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000595652	SCV002570780	benign	not specified	2022-07-12	criteria provided, single submitter	clinical testing	Variant summary: RPS6KA3 c.2168G>A (p.Arg723His) results in a non-conservative amino acid change located in the Ribosomal protein S6 kinase alpha-3, C-terminal catalytic domain (IPR041905) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 203701 control chromosomes, predominantly at a frequency of 0.0099 within the Finnish subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPS6KA3 causing Coffin-Lowry Syndrome phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=2) and benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001610515	SCV004166715	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	RPS6KA3: PP2, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003937714	SCV004753764	likely benign	RPS6KA3-related condition	2021-10-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252609	SCV001428368	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing