ClinVar Genomic variation as it relates to human health
NM_000554.6(CRX):c.121C>T (p.Arg41Trp)
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_000554.6(CRX):c.121C>T (p.Arg41Trp)
Variation ID: 7418 Accession: VCV000007418.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 47836263 (GRCh38) [ NCBI UCSC ] 19: 48339520 (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 Feb 20, 2014 Mar 10, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000554.6:c.121C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000545.1:p.Arg41Trp missense NC_000019.10:g.47836263C>T NC_000019.9:g.48339520C>T NG_008605.1:g.19422C>T O43186:p.Arg41Trp - Protein change
- R41W
- Other names
- NP_000545.1:p.(Arg41Trp)
- Canonical SPDI
- NC_000019.10:47836262: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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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CRX | - | - |
GRCh38 GRCh37 |
510 | 533 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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 (4) |
criteria provided, single submitter
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May 22, 2022 | RCV000007843.8 | |
Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
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- | RCV000085989.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV001073396.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2024 | RCV001386169.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV003324484.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV003324485.2 |
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
Help
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
Help
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
Help
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
(Jan 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001238937.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: research
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Cone-rod dystrophy
Affected status: yes
Allele origin:
germline
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Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030396.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 1
Geographic origin: Portugal
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Pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
germline
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Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030395.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 1
Geographic origin: Portugal
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Pathogenic
(Jan 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 2
Leber congenital amaurosis 7
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: SCV001586307.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 41 of the CRX protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 41 of the CRX protein (p.Arg41Trp). This variant is present in population databases (rs104894672, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal dominant CRX-related conditions (PMID: 9427255). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7418). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRX protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CRX function (PMID: 9427255). This variant disrupts the p.Arg41 amino acid residue in CRX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9427255, 10916183, 11748859, 24265693, 30543658). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002520975.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide moderate evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:9427255). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007418). A different missense change at the same codon (p.Arg41Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007421). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Rod-cone dystrophy (present)
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Dept Of Ophthalmology, Nagoya University
Accession: SCV004706290.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Pathogenic
(Dec 01, 1997)
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no assertion criteria provided
Method: literature only
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CONE-ROD DYSTROPHY 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028048.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2016 |
Comment on evidence:
In the proband from a family with autosomal dominant CORD2 (120970), Swain et al. (1997) found an arg41-to-trp substitution in the third residue of the … (more)
In the proband from a family with autosomal dominant CORD2 (120970), Swain et al. (1997) found an arg41-to-trp substitution in the third residue of the CRX homeodomain. The substitution caused a decrease in DNA binding activity. The sequence change cosegregated with the disease phenotype and was not detected in 247 normal controls. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Cone-rod dystrophy 2
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760452.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Likely 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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920939.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Cone-rod dystrophy 2
Affected status: not provided
Allele origin:
not provided
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Department of Ophthalmology and Visual Sciences Kyoto University
Accession: SCV000172551.1
First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014 |
Comment:
Converted during submission to Pathogenic.
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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: SCV001953146.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000118132.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_CRX:c.121C>T
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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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The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. | Peter VG | PNAS nexus | 2023 | PMID: 36909829 |
Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. | Birtel J | PloS one | 2018 | PMID: 30543658 |
Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. | Eisenberger T | PloS one | 2013 | PMID: 24265693 |
Novel frameshift mutations in CRX associated with Leber congenital amaurosis. | Rivolta C | Human mutation | 2001 | PMID: 11748859 |
Visual phenotype in patients with Arg41Gln and ala196+1bp mutations in the CRX gene. | Tzekov RT | Ophthalmic genetics | 2000 | PMID: 10916183 |
Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. | Swain PK | Neuron | 1997 | PMID: 9427255 |
Text-mined citations for rs104894672 ...
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.