NM_201253.3(CRB1):c.2222T>C (p.Met741Thr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 30, 2023
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:: RCV001380408.7

Allele description [Variation Report for NM_201253.3(CRB1):c.2222T>C (p.Met741Thr)]

NM_201253.3(CRB1):c.2222T>C (p.Met741Thr)

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.2222T>C (p.Met741Thr)

HGVS:

NC_000001.11:g.197427547T>C
NG_008483.2:g.231086T>C
NM_001193640.2:c.1886T>C
NM_001257965.2:c.2015T>C
NM_001257966.2:c.2128+5591T>C
NM_201253.3:c.2222T>CMANE SELECT
NP_001180569.1:p.Met629Thr
NP_001244894.1:p.Met672Thr
NP_957705.1:p.Met741Thr
NC_000001.10:g.197396677T>C
NM_201253.2:c.2222T>C
NR_047563.2:n.2175T>C
NR_047564.2:n.2383T>C
P82279:p.Met741Thr

Protein change:

M629T

Links:

UniProtKB: P82279#VAR_022956; dbSNP: rs62636267

NCBI 1000 Genomes Browser:

rs62636267

Molecular consequence:

NM_001257966.2:c.2128+5591T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001193640.2:c.1886T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257965.2:c.2015T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_201253.3:c.2222T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_047563.2:n.2175T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047564.2:n.2383T>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
SCV001578473	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15024725, 20956273, 22065545, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001578473

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 30, 2023)

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

Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis.

Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, Calvas P, Dollfus H, Hamel C, Lopponen T, Munier F, Santos L, Shalev S, Zafeiriou D, Dufier JL, Munnich A, Rozet JM, Kaplan J.

Hum Mutat. 2004 Apr;23(4):306-17.

PubMed [citation]

PMID:: 15024725

Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1.

Henderson RH, Mackay DS, Li Z, Moradi P, Sergouniotis P, Russell-Eggitt I, Thompson DA, Robson AG, Holder GE, Webster AR, Moore AT.

Br J Ophthalmol. 2011 Jun;95(6):811-7. doi: 10.1136/bjo.2010.186882. Epub 2010 Oct 17.

PubMed [citation]

PMID:: 20956273

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001578473.4

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

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 99876). This missense change has been observed in individuals with CRB1-related conditions (PMID: 15024725, 20956273, 22065545). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs62636267, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 741 of the CRB1 protein (p.Met741Thr).

#	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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