ClinVar Miner

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

dbSNP: rs1085307639
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Total submissions: 5
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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
Invitae 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).

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