VCV000801595.5 - ClinVar

NM_201253.3(CRB1):c.1313G>A (p.Cys438Tyr)

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.

(6)

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.

Uncertain significance

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.1313G>A (p.Cys438Tyr)

Variation ID: 801595 Accession: VCV000801595.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q31.3 1: 197421141 (GRCh38) [ NCBI UCSC ] 1: 197390271 (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	Jan 11, 2020	Jul 15, 2024	Apr 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_201253.3:c.1313G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_957705.1:p.Cys438Tyr	missense
NM_001193640.2:c.977G>A	NP_001180569.1:p.Cys326Tyr	missense
NM_001257965.2:c.1106G>A	NP_001244894.1:p.Cys369Tyr	missense
NM_001257966.2:c.1313G>A	NP_001244895.1:p.Cys438Tyr	missense
NR_047563.2:n.1474G>A		non-coding transcript variant
NR_047564.2:n.1474G>A		non-coding transcript variant
NC_000001.11:g.197421141G>A
NC_000001.10:g.197390271G>A
NG_008483.2:g.224680G>A

... more HGVS ... less HGVS

Protein change

C326Y, C438Y, C369Y

Other names

Canonical SPDI

NC_000001.11:197421140: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.

Links

dbSNP: rs1571522690 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 1	Uncertain significance (1)	criteria provided, single submitter	May 28, 2019	RCV000986487.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 14, 2018	RCV001759677.2
Retinitis pigmentosa 12	Uncertain significance (1)	criteria provided, single submitter	Apr 11, 2023	RCV003454998.1
Leber congenital amaurosis 8	Uncertain significance (1)	criteria provided, single submitter	Apr 11, 2023	RCV003454999.1
Pigmented paravenous retinochoroidal atrophy	Uncertain significance (1)	criteria provided, single submitter	Apr 11, 2023	RCV003455000.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 30, 2024	RCV004586998.1

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.
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Leber congenital amaurosis 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135499.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020
Uncertain significance (Dec 14, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001985385.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more) Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29053603, 17724218) (less)
Uncertain significance (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: SCV004179901.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (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: SCV004179902.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (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: SCV004179904.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (Apr 30, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005076279.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (3) PubMed: 29053603‚ 36460718‚ 17724218 Comment: Variant summary: CRB1 c.1313G>A (p.Cys438Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: CRB1 c.1313G>A (p.Cys438Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes. c.1313G>A has been reported in the literature in individuals affected with Retinal Dystrophy and related conditions (Di Lorio_2017, Simonelli_2017, Karali_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29053603, 36460718, 17724218).ClinVar contains an entry for this variant (Variation ID: 801595). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)

Comment:

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29053603, 17724218)

Comment:

Variant summary: CRB1 c.1313G>A (p.Cys438Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes. c.1313G>A has been reported in the literature in individuals affected with Retinal Dystrophy and related conditions (Di Lorio_2017, Simonelli_2017, Karali_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29053603, 36460718, 17724218).ClinVar contains an entry for this variant (Variation ID: 801595). Based on the evidence outlined above, the variant was classified as VUS-possibly 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
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies.	Di Iorio V	Genes	2017	PMID: 29053603
Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients.	Simonelli F	Investigative ophthalmology & visual science	2007	PMID: 17724218

Text-mined citations for rs1571522690 ...

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 Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_201253.3(CRB1):c.1313G>A (p.Cys438Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1571522690 ...