Submissions for variant NM_004586.3(RPS6KA3):c.1894C>T (p.Arg632Ter)

dbSNP: rs1085307639

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489984	SCV000576914	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32371413, 31130284, 29304373)
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249648	SCV001423707	pathogenic	Coffin-Lowry syndrome	2017-10-16	criteria provided, single submitter	clinical testing	[ACMG/AMP: PVS1, PS2, PM2, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249648	SCV002556013	pathogenic	Coffin-Lowry syndrome	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: RPS6KA3 c.1894C>T (p.Arg632X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic (e.g c.1934G>A (p.Trp645X); c.1996C>T (p.Gln666X); c.2065C>T (p.Gln689X); ClinVar). The variant was absent in 179201 control chromosomes. c.1894C>T has been reported in the literature in individuals affected with Coffin-Lowry Syndrome (e.g. Aref-Eshghi_2018, Monies_2019, Miller_2020) including one case where it was confirmed to be de novo (Miller_2020). These data indicate that the variant is very likely associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001249648	SCV002764859	pathogenic	Coffin-Lowry syndrome	2022-07-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002523411	SCV003444432	pathogenic	Coffin-Lowry syndrome; Intellectual disability, X-linked 19	2022-07-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426465). This premature translational stop signal has been observed in individual(s) with clinical features of Coffin-Lowry syndrome (PMID: 29304373, 31130284, 32371413). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg632*) in the RPS6KA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPS6KA3 are known to be pathogenic (PMID: 9837815, 19888300).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001249648	SCV004847321	pathogenic	Coffin-Lowry syndrome	2023-08-16	criteria provided, single submitter	clinical testing	The c.1894C>T (p.Arg632X) variant in RPS6KA3 has been previously reported in 3 individuals with Coffin-Lowry Syndrome, one of which was confirmed to be de novo (Aref-Eshghi 2018 PMID: 29304373, Monies 2019 PMID: 31130284, Miller 2020 PMID: 32371413). This variant was absent from large population studies (gnomAD). This variant has also been reported in ClinVar (Variation ID: 426465). This nonsense variant leads to a premature termination codon at position 632, which is predicted to lead to a truncated or absent protein. Loss of function of the RPS6KA3 gene is an established disease mechanism in X-linked Coffin-Lowry Syndrome (Jacquot 1998 PMID: 9837815, Delaunoy 2006 PMID: 16879200). In summary, this variant meets criteria to be classified as pathogenic for X-linked Coffin-Lowry Syndrome. ACMG/AMP Criteria applied: PVS1, PS2, PS4_Moderate, PM2_Supporting.