ClinVar Genomic variation as it relates to human health
NM_004586.3(RPS6KA3):c.1894C>T (p.Arg632Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004586.3(RPS6KA3):c.1894C>T (p.Arg632Ter)
Variation ID: 426465 Accession: VCV000426465.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.12 X: 20161709 (GRCh38) [ NCBI UCSC ] X: 20179827 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 22, 2017 Apr 20, 2024 Aug 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004586.3:c.1894C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004577.1:p.Arg632Ter nonsense NC_000023.11:g.20161709G>A NC_000023.10:g.20179827G>A NG_007488.1:g.109924C>T - Protein change
- R632*
- Other names
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- Canonical SPDI
- NC_000023.11:20161708:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RPS6KA3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
399 | 579 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2022 | RCV000489984.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV001249648.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 11, 2022 | RCV002523411.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000576914.6
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Oct 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Coffin-Lowry syndrome
Affected status: yes
Allele origin:
germline
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Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423707.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
Comment:
[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 … (more)
[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]. (less)
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Pathogenic
(Jun 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Coffin-Lowry syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556013.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Coffin-Lowry syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764859.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present) , Abnormal facial shape (present) , Global developmental delay (present) , Leukodystrophy (present)
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Pathogenic
(Jul 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Coffin-Lowry syndrome
Intellectual disability, X-linked 19
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003444432.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Coffin-Lowry syndrome
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847321.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience. | Miller CR | Cold Spring Harbor molecular case studies | 2020 | PMID: 32371413 |
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes. | Aref-Eshghi E | American journal of human genetics | 2018 | PMID: 29304373 |
Coffin-Lowry syndrome. | Pereira PM | European journal of human genetics : EJHG | 2010 | PMID: 19888300 |
Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome. | Delaunoy JP | Clinical genetics | 2006 | PMID: 16879200 |
Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. | Jacquot S | American journal of human genetics | 1998 | PMID: 9837815 |
Text-mined citations for rs1085307639 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.