NM_201253.3(CRB1):c.1439G>C (p.Cys480Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 10, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001378739.5

Allele description [Variation Report for NM_201253.3(CRB1):c.1439G>C (p.Cys480Ser)]

NM_201253.3(CRB1):c.1439G>C (p.Cys480Ser)

Gene:

CRB1:crumbs cell polarity complex component 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q31.3

Genomic location:

Preferred name:

NM_201253.3(CRB1):c.1439G>C (p.Cys480Ser)

HGVS:

NC_000001.11:g.197421267G>C
NG_008483.2:g.224806G>C
NM_001193640.2:c.1103G>C
NM_001257965.2:c.1232G>C
NM_001257966.2:c.1439G>C
NM_201253.3:c.1439G>CMANE SELECT
NP_001180569.1:p.Cys368Ser
NP_001244894.1:p.Cys411Ser
NP_001244895.1:p.Cys480Ser
NP_957705.1:p.Cys480Ser
NC_000001.10:g.197390397G>C
NR_047563.2:n.1600G>C
NR_047564.2:n.1600G>C

Protein change:

C368S

Links:

dbSNP: rs62636265

NCBI 1000 Genomes Browser:

rs62636265

Molecular consequence:

NM_001193640.2:c.1103G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257965.2:c.1232G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257966.2:c.1439G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_201253.3:c.1439G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_047563.2:n.1600G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047564.2:n.1600G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Retinitis pigmentosa 12 (RP12)
Synonyms:: RP 12; RP WITH OR WITHOUT PPRPE; RP WITH OR WITHOUT PRESERVED PARAARTERIOLE RETINAL PIGMENT EPITHELIUM; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010818; MedGen: C1838647; Orphanet: 791; OMIM: 600105

Name:: Leber congenital amaurosis 8 (LCA8)
Identifiers:: MONDO: MONDO:0013453; MedGen: C3151202; Orphanet: 65; OMIM: 613835

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001576378	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 10, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11231775, 21757580, 23847139, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001576378

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 10, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the CRB1 gene cause Leber congenital amaurosis.

Lotery AJ, Jacobson SG, Fishman GA, Weleber RG, Fulton AB, Namperumalsamy P, Héon E, Levin AV, Grover S, Rosenow JR, Kopp KK, Sheffield VC, Stone EM.

Arch Ophthalmol. 2001 Mar;119(3):415-20.

PubMed [citation]

PMID:: 11231775

Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model.

Aleman TS, Cideciyan AV, Aguirre GK, Huang WC, Mullins CL, Roman AJ, Sumaroka A, Olivares MB, Tsai FF, Schwartz SB, Vandenberghe LH, Limberis MP, Stone EM, Bell P, Wilson JM, Jacobson SG.

Invest Ophthalmol Vis Sci. 2011 Aug 29;52(9):6898-910. doi: 10.1167/iovs.11-7701.

PubMed [citation]

PMID:: 21757580
PMCID:: PMC3176016

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001576378.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 480 of the CRB1 protein (p.Cys480Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with Leber congenital amaurosis or retinitis pigmentosa (PMID: 23847139; Invitae). ClinVar contains an entry for this variant (Variation ID: 1067463). 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 CRB1 protein function. This variant disrupts the p.Cys480 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11231775, 21757580, 23847139). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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