VCV000039614.69 - ClinVar

NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)

Germline

Classification

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.

(32)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)

Variation ID: 39614 Accession: VCV000039614.69

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q31.3 1: 197434706 (GRCh38) [ NCBI UCSC ] 1: 197403836 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 1, 2013	Oct 20, 2024	Mar 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_201253.3:c.2843G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_957705.1:p.Cys948Tyr	missense
NM_001193640.2:c.2507G>A	NP_001180569.1:p.Cys836Tyr	missense
NM_001257965.2:c.2771G>A	NP_001244894.1:p.Cys924Tyr	missense
NM_001257966.2:c.2129-894G>A		intron variant
NR_047563.2:n.2796G>A		non-coding transcript variant
NR_047564.2:n.3004G>A		non-coding transcript variant
NC_000001.11:g.197434706G>A
NC_000001.10:g.197403836G>A
NG_008483.2:g.238245G>A
	P82279:p.Cys948Tyr

... more HGVS ... less HGVS

Protein change

C948Y, C836Y, C924Y

Other names

NP_957705.1:p.(Cys948Tyr)

Canonical SPDI

NC_000001.11:197434705:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00013

Exome Aggregation Consortium (ExAC) 0.00021

The Genome Aggregation Database (gnomAD), exomes 0.00021

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00023

Links

ClinGen: CA228022 UniProtKB: P82279#VAR_011645 OMIM: 604210.0013 dbSNP: rs62645748 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
CRB1		-	-	GRCh38 GRCh37	1943	1968

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 Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Leber congenital amaurosis 8	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 28, 2024	RCV000032814.15
Retinitis pigmentosa 12	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000032815.17
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 31, 2022	RCV000086331.41
Leber congenital amaurosis 8 Retinitis pigmentosa 12	Pathogenic (1)	criteria provided, single submitter	Jan 7, 2024	RCV000554663.12
Retinal dystrophy	Pathogenic (2)	criteria provided, single submitter	Jun 25, 2019	RCV000505155.7
Leber congenital amaurosis 8 Pigmented paravenous retinochoroidal atrophy Retinitis pigmentosa 12	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762874.6
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787579.4
Pigmented paravenous retinochoroidal atrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV001097540.11
Leber congenital amaurosis	Pathogenic (2)	criteria provided, single submitter	Jul 24, 2023	RCV001275657.5
CRB1-related disorder	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV003313928.7
Cone dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324500.5
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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.
Pathogenic (Dec 04, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	CRB1-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914377.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 20956273‚ 20301475‚ 11231775‚ 23379534‚ 10508521 Comment: The CRB1 c.2843G>A (p.Cys948Tyr) missense variant is described as the most common variant in individuals with Leber congenital amaurosis (LCA), detected in approximately 20% of … (more) The CRB1 c.2843G>A (p.Cys948Tyr) missense variant is described as the most common variant in individuals with Leber congenital amaurosis (LCA), detected in approximately 20% of probands (Weleber et al 2013). The p.Cys948Tyr variant has been reported in at least four studies in a total of 36 probands with either LCA or retinitis pigmentosa, including in six probands in a homozygous state, in 25 in a compound heterozygous state and in five in a heterozygous state with an unidentified second variant (den Hollander et al. 1999; Lotery et al. 2001; Henderson et al. 2011; Corton et al. 2013). The p.Cys948Tyr variant was absent from 240 unaffected control individuals and is reported at a frequency of 0.000397 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Cys948Tyr variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmented paravenous retinochoroidal atrophy Retinitis pigmentosa 12 Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893254.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jul 18, 2020)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135506.2 First in ClinVar: Jan 09, 2020 Last updated: Jul 25, 2020
Pathogenic (Feb 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 12 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV003804626.2 First in ClinVar: Mar 04, 2023 Last updated: May 27, 2023	Clinical Features: Rod-cone dystrophy (present) , Cataract (present) , Blindness (present)
Pathogenic (Dec 28, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001801230.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: One of the most common pathogenic variants reported in the CRB1 gene, accounting for up to 24% of disease-causing alleles in some studies (Bujakowska et … (more) One of the most common pathogenic variants reported in the CRB1 gene, accounting for up to 24% of disease-causing alleles in some studies (Bujakowska et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19401883, 23379534, 25474345, 12700176, 16205573, 16272259, 16505055, 18055816, 18055820, 18334942, 20591486, 20683928, 21757580, 24512366, 24516651, 25342620, 23591405, 11389483, 15459956, 12843338, 10508521, 20956273, 15024725, 11231775, 27113771, 26914788, 28181551, 28341475, 28341476, 22065545, 29178642, 29343940, 28157192, 30576320, 30337596, 30718709, 28559085, 32141364, 32581362, 31589614, 33576794, 33029571, 32865313) (less)
Pathogenic (May 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CRB1-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004013162.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PM1, PM2, PM3_Very Strong, PM5, PP3
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leber congenital amaurosis Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030390.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PP3, PM2, PM5, PS4, PP2.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Geographic origin: Portugal
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cone dystrophy Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030391.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PP3, PM2, PM5, PS4, PP2.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Geographic origin: Portugal
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 12 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004180095.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004180093.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmented paravenous retinochoroidal atrophy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004180094.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003819340.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001524218.2 First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024
Pathogenic (Nov 14, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000343269.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 10508521‚ 23379534‚ 24512366 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRB1 Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Jun 25, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241395.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmented paravenous retinochoroidal atrophy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366463.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5.
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Retinitis pigmentosa 12 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760000.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021
Pathogenic (May 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 12 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580105.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM3_VSTR, PS4, PM5, PP1, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (Jan 07, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 8 Retinitis pigmentosa 12 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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000650638.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 10508521‚ 18055816‚ 19401883‚ 20956273‚ 23379534‚ 24512366‚ 27113771 Comment: This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 948 of the CRB1 protein … (more) This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 948 of the CRB1 protein (p.Cys948Tyr). This variant is present in population databases (rs62645748, gnomAD 0.04%). This missense change has been observed in individuals with Leber congenital amaurosis, early-onset retinal dystrophy, and retinitis pigmentosa (PMID: 10508521, 18055816, 19401883, 20956273, 23379534, 24512366, 27113771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39614). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248714.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 4
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001954033.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Mar 01, 2001)	no assertion criteria provided Method: literature only	LEBER CONGENITAL AMAUROSIS 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056582.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2015	Publications: PubMed (2) PubMed: 11231775‚ 10508521 Comment on evidence: In 7 patients with Leber congenital amaurosis (LCA8; 613835), Lotery et al. (2001) identified a G-A transition in the CRB1 gene that resulted in a … (more) In 7 patients with Leber congenital amaurosis (LCA8; 613835), Lotery et al. (2001) identified a G-A transition in the CRB1 gene that resulted in a cys948-to-tyr (C948Y) substitution. The mutation was present in homozygosity in 1 patient, in compound heterozygosity with a missense and a frameshift mutation in 2 patients, respectively, and in heterozygosity in 4 patients. The mutation was not found in 280 control alleles. Lotery et al. (2001) noted that C948Y had previously been reported in patients with retinitis pigmentosa (RP12; 600105) by den Hollander et al. (1999). (less)
Pathogenic (Mar 01, 2001)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 12 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056583.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2015	Publications: PubMed (2) PubMed: 11231775‚ 10508521 Comment on evidence: In 7 patients with Leber congenital amaurosis (LCA8; 613835), Lotery et al. (2001) identified a G-A transition in the CRB1 gene that resulted in a … (more) In 7 patients with Leber congenital amaurosis (LCA8; 613835), Lotery et al. (2001) identified a G-A transition in the CRB1 gene that resulted in a cys948-to-tyr (C948Y) substitution. The mutation was present in homozygosity in 1 patient, in compound heterozygosity with a missense and a frameshift mutation in 2 patients, respectively, and in heterozygosity in 4 patients. The mutation was not found in 280 control alleles. Lotery et al. (2001) noted that C948Y had previously been reported in patients with retinitis pigmentosa (RP12; 600105) by den Hollander et al. (1999). (less)
Pathogenic (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 8 Affected status: yes Allele origin: inherited	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001425478.1 First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020	Publications: PubMed (1) PubMed: 10508521 Number of individuals with the variant: 15
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460948.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917492.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001969278.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinal dystrophy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598920.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 10508521 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926559.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Sep 03, 2024)	no assertion criteria provided Method: clinical testing	CRB1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004779697.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The CRB1 c.2843G>A variant is predicted to result in the amino acid substitution p.Cys948Tyr. This variant has been reported in the homozygous and compound heterozygous … (more) The CRB1 c.2843G>A variant is predicted to result in the amino acid substitution p.Cys948Tyr. This variant has been reported in the homozygous and compound heterozygous states to be causative for retinal dystrophy (see examples den Hollander et al. 1999. PubMed ID: 10508521; Lotery et al. 2001. PubMed ID: 11231775; Zaneveld et al. 2015. PubMed ID: 25474345). This variant is documented in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/39614/). We interpret c.2843G>A (p.Cys948Tyr) as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Leber congenital amaurosis 8 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000087117.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301475 BookShelf: NBK1298 BookShelf: NBK1298
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000118477.1 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_CRB1:c.2843G>A
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Comment:

The CRB1 c.2843G>A (p.Cys948Tyr) missense variant is described as the most common variant in individuals with Leber congenital amaurosis (LCA), detected in approximately 20% of probands (Weleber et al 2013). The p.Cys948Tyr variant has been reported in at least four studies in a total of 36 probands with either LCA or retinitis pigmentosa, including in six probands in a homozygous state, in 25 in a compound heterozygous state and in five in a heterozygous state with an unidentified second variant (den Hollander et al. 1999; Lotery et al. 2001; Henderson et al. 2011; Corton et al. 2013). The p.Cys948Tyr variant was absent from 240 unaffected control individuals and is reported at a frequency of 0.000397 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Cys948Tyr variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

One of the most common pathogenic variants reported in the CRB1 gene, accounting for up to 24% of disease-causing alleles in some studies (Bujakowska et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19401883, 23379534, 25474345, 12700176, 16205573, 16272259, 16505055, 18055816, 18055820, 18334942, 20591486, 20683928, 21757580, 24512366, 24516651, 25342620, 23591405, 11389483, 15459956, 12843338, 10508521, 20956273, 15024725, 11231775, 27113771, 26914788, 28181551, 28341475, 28341476, 22065545, 29178642, 29343940, 28157192, 30576320, 30337596, 30718709, 28559085, 32141364, 32581362, 31589614, 33576794, 33029571, 32865313)

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 948 of the CRB1 protein (p.Cys948Tyr). This variant is present in population databases (rs62645748, gnomAD 0.04%). This missense change has been observed in individuals with Leber congenital amaurosis, early-onset retinal dystrophy, and retinitis pigmentosa (PMID: 10508521, 18055816, 19401883, 20956273, 23379534, 24512366, 27113771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39614). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The CRB1 c.2843G>A variant is predicted to result in the amino acid substitution p.Cys948Tyr. This variant has been reported in the homozygous and compound heterozygous states to be causative for retinal dystrophy (see examples den Hollander et al. 1999. PubMed ID: 10508521; Lotery et al. 2001. PubMed ID: 11231775; Zaneveld et al. 2015. PubMed ID: 25474345). This variant is documented in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/39614/). We interpret c.2843G>A (p.Cys948Tyr) as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Molecular and clinical analysis of 27 German patients with Leber congenital amaurosis.	Weisschuh N	PloS one	2018	PMID: 30576320
Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants.	Kousal B	Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie	2016	PMID: 27113771
Retinal Dystrophy with Intraretinal Cystoid Spaces Associated with Mutations in the Crumbs Homologue (CRB1) Gene.	Cordovez JA	Ophthalmic genetics	2015	PMID: 24512366
High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population.	Corton M	Orphanet journal of rare diseases	2013	PMID: 23379534
Leber Congenital Amaurosis – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301475
Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1.	Henderson RH	The British journal of ophthalmology	2011	PMID: 20956273
Case report: autofluorescence imaging and phenotypic variance in a sibling pair with early-onset retinal dystrophy due to defective CRB1 function.	Tosi J	Current eye research	2009	PMID: 19401883
Mutation screening of 299 Spanish families with retinal dystrophies by Leber congenital amaurosis genotyping microarray.	Vallespin E	Investigative ophthalmology & visual science	2007	PMID: 18055816
Mutations in the CRB1 gene cause Leber congenital amaurosis.	Lotery AJ	Archives of ophthalmology (Chicago, Ill. : 1960)	2001	PMID: 11231775
Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).	den Hollander AI	Nature genetics	1999	PMID: 10508521
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRB1	-	-	-	-
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Text-mined citations for rs62645748 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62645748 ...