ClinVar Genomic variation as it relates to human health
NM_006915.3(RP2):c.8G>C (p.Cys3Ser)
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.
Likely pathogenic(1); Uncertain significance(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006915.3(RP2):c.8G>C (p.Cys3Ser)
Variation ID: 418458 Accession: VCV000418458.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.3 X: 46837108 (GRCh38) [ NCBI UCSC ] X: 46696543 (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 Apr 27, 2017 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006915.3:c.8G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008846.2:p.Cys3Ser missense NC_000023.11:g.46837108G>C NC_000023.10:g.46696543G>C NG_009107.1:g.5197G>C - Protein change
- C3S
- Other names
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- Canonical SPDI
- NC_000023.11:46837107:G:C
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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.
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
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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RP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
355 | 562 | |
LOC130068202 | - | - | - | GRCh38 | - | 122 |
Conditions - Germline
Condition
Help
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000479201.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 24, 2022 | RCV002470866.2 |
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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Likely pathogenic
(Mar 27, 2017)
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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: SCV000565493.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The C3S variant in the RP2 gene has been reported previously in the hemizygous state in a male with retinitis pigmentosa (Jayasundera et al., 2010). … (more)
The C3S variant in the RP2 gene has been reported previously in the hemizygous state in a male with retinitis pigmentosa (Jayasundera et al., 2010). The C3S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C3S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies demonstrate that C3S is associated with abnormal RP2 protein localization (Chapple et al., 2000). Therefore, we interpret C3S as a likely pathogenic variant. (less)
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Uncertain significance
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 2
(X-linked recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768013.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. The following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 2 (MIM# 312600). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (4 heterozygotes, 0 homozygotes, 3 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the N-terminal consensus myristoylation and palmitoylation motif where the cysteine-3 amino acid represents the site of palmitoylation (PMID 10942419, 12037013, Uniprot). (SP) 0803 - This variant has limited previous evidence of pathogenicity. This variant has previously been reported as likely pathogenic (ClinVar) and in a patient with X-linked retinitis pigmentosa (PMIDs: 20625056, 23150612). It has also been reported in the homozygous state in a female patient with HYAL deficiency where this variant was thought to explain the severity of this patient's ocular phenotype. However, this patient underwent exome sequencing at the laboratory who submitted the ClinVar entry; therefore it is unclear if this is an additional patient (PMID: 34906488). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function where this variant was shown to result in protein mislocalization (PMIDs: 10942419, 12037013, 22072390, 28209709, 20729296, 20106869). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003444652.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
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Uncertain significance
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822019.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
RP2: PS4:Moderate, PP4, PS3:Supporting
Number of individuals with the variant: 1
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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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Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency. | Fasham J | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906488 |
Pathogenic mutations in retinitis pigmentosa 2 predominantly result in loss of RP2 protein stability in humans and zebrafish. | Liu F | The Journal of biological chemistry | 2017 | PMID: 28209709 |
The X-linked retinitis pigmentosa protein RP2 facilitates G protein traffic. | Schwarz N | Human molecular genetics | 2012 | PMID: 22072390 |
The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development. | Hurd T | Human molecular genetics | 2010 | PMID: 20729296 |
The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. | Evans RJ | Human molecular genetics | 2010 | PMID: 20106869 |
Delineation of the plasma membrane targeting domain of the X-linked retinitis pigmentosa protein RP2. | Chapple JP | Investigative ophthalmology & visual science | 2002 | PMID: 12037013 |
Mutations in the N-terminus of the X-linked retinitis pigmentosa protein RP2 interfere with the normal targeting of the protein to the plasma membrane. | Chapple JP | Human molecular genetics | 2000 | PMID: 10942419 |
Text-mined citations for rs782344765 ...
HelpRecord last updated Apr 15, 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.