ClinVar Genomic variation as it relates to human health
NM_145200.5(CABP4):c.646C>T (p.Arg216Ter)
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_145200.5(CABP4):c.646C>T (p.Arg216Ter)
Variation ID: 190959 Accession: VCV000190959.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 67457677 (GRCh38) [ NCBI UCSC ] 11: 67225148 (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 24, 2015 Feb 20, 2024 Oct 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_145200.5:c.646C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_660201.1:p.Arg216Ter nonsense NM_001300895.3:c.331C>T NP_001287824.1:p.Arg111Ter nonsense NM_001300896.3:c.331C>T NP_001287825.1:p.Arg111Ter nonsense NM_001379183.1:c.331C>T NP_001366112.1:p.Arg111Ter nonsense NR_166529.1:n.541C>T non-coding transcript variant NC_000011.10:g.67457677C>T NC_000011.9:g.67225148C>T NG_021211.1:g.7331C>T - Protein change
- R216*, R111*
- Other names
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- Canonical SPDI
- NC_000011.10:67457676:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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CABP4 | - | - |
GRCh38 GRCh37 |
380 | 407 |
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 (3) |
criteria provided, single submitter
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Oct 15, 2020 | RCV000171132.11 | |
Likely pathogenic (1) |
no assertion criteria provided
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Apr 1, 2018 | RCV000787550.2 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2018 | RCV000787800.2 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000760417.11 |
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
(Oct 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod synaptic disorder, congenital nonprogressive
(Autosomal 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: SCV002768612.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital nonprogressive cone-rod synaptic disorder (MIM#610427). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). Functional analysis of patient cell-derived RNA suggests NMD-escape, however these results are inconclusive (PMID: 19074807). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants have also been reported in patients with retinal conditions (ClinVar, PMID: 29706639). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and in both homozygous and compound heterozygous patients with cone-rod disorders, retinal diseases and achromatopsia (ClinVar, PMID: 19074807, PMID: 29525873, PMID: 30718709). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001669). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Oct 03, 2023)
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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: SCV001393898.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg216*) in the CABP4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg216*) in the CABP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CABP4 are known to be pathogenic (PMID: 25307992). This variant is present in population databases (rs150115958, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinal disease and/or autosomal recessive cone-rod synaptic disorder (PMID: 19074807, 29525873). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190959). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 08, 2018)
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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: SCV000890295.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Comment:
he R216X variant in the CABP4 gene has been reported previously in association with autosomal recessive cone-rod synaptic disorder when present in the homozygous state … (more)
he R216X variant in the CABP4 gene has been reported previously in association with autosomal recessive cone-rod synaptic disorder when present in the homozygous state or when in trans with another disease causing variant (Littink et al., 2009; Smirnov et al., 2018). This variant is predicted to cause loss of normal protein function through protein truncation (Littink et al., 2009). Functional studies demonstrate a damaging effect with reduction in Ca(2+) channel availability and loss of Ca(2+) channel function (Shaltiel et al., 2012). The R216X variant is observed in 2/16,714 (0.012%) alleles from individuals of Finnish European background and in 11/188,328 (0.0058%) global alleles in large population cohorts (Lek et al., 2016). We interpret R216X as a pathogenic variant. (less)
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Pathogenic
(Oct 01, 2013)
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no assertion criteria provided
Method: literature only
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CONE-ROD SYNAPTIC DISORDER, CONGENITAL NONPROGRESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000223699.1
First in ClinVar: May 24, 2015 Last updated: May 24, 2015 |
Comment on evidence:
In a Dutch brother and sister with congenital nonprogressive cone-rod synaptic disorder (CRSD; 610427), Littink et al. (2009) identified homozygosity for a c.646C-T transition (c.646C-T, … (more)
In a Dutch brother and sister with congenital nonprogressive cone-rod synaptic disorder (CRSD; 610427), Littink et al. (2009) identified homozygosity for a c.646C-T transition (c.646C-T, NM_14500) in exon 4 of the CABP4 gene, resulting in an arg216-to-ter (R216X) substitution that deletes the functional EF-hands 3 and 4. The unaffected parents were heterozygous for the mutation, which was not found in 300 ethnically matched alleles. In a female Dutch patient with low visual acuity, hyperopia, severe nonspecific color vision defects, and photophobia, Bijveld et al. (2013) identified homozygosity for the R216X mutation in CABP4. (less)
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Pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Cone-rod synaptic disorder, congenital nonprogressive
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804603.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Cone-rod dystrophy
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926525.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Achromatopsia
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926810.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956262.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967411.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population. | Hanany M | European journal of human genetics : EJHG | 2018 | PMID: 29706639 |
Retinal findings in a patient of French ancestry with CABP4-related retinal disease. | Smirnov VM | Documenta ophthalmologica. Advances in ophthalmology | 2018 | PMID: 29525873 |
Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms. | Zeitz C | Progress in retinal and eye research | 2015 | PMID: 25307992 |
Genotype and phenotype of 101 dutch patients with congenital stationary night blindness. | Bijveld MM | Ophthalmology | 2013 | PMID: 23714322 |
A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder. | Littink KW | Investigative ophthalmology & visual science | 2009 | PMID: 19074807 |
Text-mined citations for rs150115958 ...
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.