NM_201253.3(CRB1):c.2054G>C (p.Gly685Ala) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 2, 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:: RCV002633018.2

Allele description [Variation Report for NM_201253.3(CRB1):c.2054G>C (p.Gly685Ala)]

NM_201253.3(CRB1):c.2054G>C (p.Gly685Ala)

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.2054G>C (p.Gly685Ala)

HGVS:

NC_000001.11:g.197421882G>C
NG_008483.3:g.225380G>C
NM_001193640.2:c.1718G>C
NM_001257965.2:c.1847G>C
NM_001257966.2:c.2054G>C
NM_201253.3:c.2054G>CMANE SELECT
NP_001180569.1:p.Gly573Ala
NP_001244894.1:p.Gly616Ala
NP_001244895.1:p.Gly685Ala
NP_957705.1:p.Gly685Ala
NC_000001.10:g.197391012G>C
NG_008483.2:g.225421G>C
NR_047563.2:n.2007G>C
NR_047564.2:n.2215G>C

Protein change:

G573A

Molecular consequence:

NM_001193640.2:c.1718G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257965.2:c.1847G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001257966.2:c.2054G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_201253.3:c.2054G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_047563.2:n.2007G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047564.2:n.2215G>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
SCV003511672	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30902645, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003511672

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 2, 2023)

germline

clinical testing

PubMed (2)
[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

Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases.

Martin-Merida I, Avila-Fernandez A, Del Pozo-Valero M, Blanco-Kelly F, Zurita O, Perez-Carro R, Aguilera-Garcia D, Riveiro-Alvarez R, Arteche A, Trujillo-Tiebas MJ, Tahsin-Swafiri S, Rodriguez-Pinilla E, Lorda-Sanchez I, Garcia-Sandoval B, Corton M, Ayuso C.

Ophthalmology. 2019 Aug;126(8):1181-1188. doi: 10.1016/j.ophtha.2019.03.018. Epub 2019 Mar 20.

PubMed [citation]

PMID:: 30902645

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003511672.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 685 of the CRB1 protein (p.Gly685Ala). This variant is present in population databases (rs748175297, gnomAD 0.003%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 30902645). ClinVar contains an entry for this variant (Variation ID: 2191841). 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 with a positive predictive value of 80%. This variant disrupts the p.Gly685 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 30902645; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Mar 5, 2024

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