High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population

Corton, Marta; Tatu, Sorina D; Avila-Fernandez, Almudena; Vallespín, Elena; Tapias, Ignacio; Cantalapiedra, Diego; Blanco-Kelly, Fiona; Riveiro-Alvarez, Rosa; Bernal, Sara; García-Sandoval, Blanca; Baiget, Montserrat; Ayuso, Carmen

doi:10.1186/1750-1172-8-20

Orphanet Journal of Rare Diseases

Table 3 List of novel CRB1 likeky pathogenic variants identified in the studied cohort

From: High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population

Nucleotide change	AA change	Protein	Conservation	SIFT score	Polyphen score	GD-GV score	PROVEAN score	Pathogenicity
		Domain
*Missense*
c.1604 T > C	p.Leu535Pro	Lam AG1	HC	0	1	Class C65	-6.5	Likely
c.1690G > T	p.Asp564Tyr	Lam AG1	HC	0	1	Class C65	-8.2	Likely
c.1702C > T	p.His568Tyr	Lam AG1	HC	0	0.999	Class C65	-5.0	Likely
c.2291G > A	p.Arg764His	Lam AG2	NC	0.06	0.012	Class C0	-2.3	Uncertain ^a
c.2309 G > T	p.Gly770Val	Lam AG2	HC	0	1	Class C65	-8.2	Likely
c.2696 G > C*	p.Gly899Ala	EGF13	HC	0.1	0.996	Class C0	-4.5	Likely
c.3002A > T	p.Ile1001Asn	Lam AG3	MC	0.0	0.850	Class C45	-5.5	Likely
c.3014 A > T	p.Asp1005Val	Lam AG3	WC	0.02	0.996	Class C15	-5.0	Likely
c.3157 A > G	p.Met1053Val	Lam AG3	HC	0	0.994	Class C15	-2.2	Likely
c.3299 T > C	p.Ile1100Thr	Lam AG3	C	0	0.977	Class C25	-3.6	Likely
c.3482A > G	p.Tyr1161Cys	EGF15	MC	0	0.999	Class C15	-6.1	Likely
*Nonsense*
c.2416G > T	p.Glu806*	Lam AG2	Protein truncation, NMD
c.2465G > A	p.Trp822*	Lam AG2	Protein truncation, NMD
c.3152G > A	p.Trp1051*	Lam AG3	Protein truncation, NMD
c.3607 G > T	p.Glu1203*	EGF16	Protein truncation, NMD
c.3988G > T	p.Glu1330*	EGF19	Protein truncation, NMD
c.4168C > T	p.Arg1390*	C	Protein truncation
*Frameshift indels*
c.481dupG	p.Ala161Glyfs*8	EGF4	Protein truncation, NMD
c.1147_1156del	p.Cys383Serfs*66	EGF9	Protein truncation, NMD
c.2227delG	p.Val743Serfs*11	Lam AG2	Protein truncation, NMD
c.2805dupA	p.His935Glnfs*13	EGF14	Protein truncation, NMD
c.4000delG	p.Val1334Trpfs*7	EGF19	Protein truncation, NMD
*Splicing*
c.3749 + 1_3749 + 2del	-	EGF17	Splicing defect, NMD
c.3878 + 2insT	Splicing	EGF18	Splicing defect, NMD
In-frame indel
c.2244_47delATC	p.Ser749del	Lam AG2	WC				-11.453	Likely
c.498_506del	p.Ile167_Gly169del	EGF4	Gly167: MC				-14.258	Likely

Nucleotide numbering is based on RefSeq DNA accession number NM_201253.1. Lam AG: Laminin AG-like domain, EGF: EGF-like domain, C: cytoplasmatic domain. Conservation of the amino acid substituted or deleted in 17 species was detailed. HC: Highly conserved, MC: Moderately conserved, WC: Weakly conserved, and NC: non-conserved residue. The amino acid substitution is predicted damaging by if the SIFT score is < = 0.05 and PROVEAN scores is < -2.5. Polyphen predict a non-synonymous variant as benign, possibly damaging, or probably damaging, if score is < 0.2, between 0.2 and 0.85 or > 0.85. GV: Grantham Variation; GD: Grantham distribution. Class C65: most likely pathogenic, Class C0: less likely pathogenic.
^a This variant has been considered as likely pathogenic despite of poor conservation and less likely pathogenicity with four predictive tools. This variant was found associated with a second allele. It was absent in healthy control alleles but reported in ESP project (1/4405). Moreover, a known mutation Arg764Cys was reported in the same residue.

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ISSN: 1750-1172

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