rs62635659

Positions:

• chr1-197435162-T-C
• chr1-197435162-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_201253.3(CRB1):​c.3299T>C​(p.Ile1100Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1100R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.47

Genes affected

CRB1 (HGNC:2343): (crumbs cell polarity complex component 1) This gene encodes a protein which is similar to the Drosophila crumbs protein and localizes to the inner segment of mammalian photoreceptors. In Drosophila crumbs localizes to the stalk of the fly photoreceptor and may be a component of the molecular scaffold that controls proper development of polarity in the eye. Mutations in this gene are associated with a severe form of retinitis pigmentosa, RP12, and with Leber congenital amaurosis. Alternate splicing results in multiple transcript variants, some protein coding and some non-protein coding.[provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-197435162-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5734.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 1-197435162-T-C is Pathogenic according to our data. Variant chr1-197435162-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197435162-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-197435162-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.3299T>C	p.Ile1100Thr	missense_variant	9/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.3299T>C	p.Ile1100Thr	missense_variant	9/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461636 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 8 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Pigmented paravenous retinochoroidal atrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2022

This variant is present in population databases (rs62635659, gnomAD 0.004%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1100 of the CRB1 protein (p.Ile1100Thr). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa and/or Leber congenital amaurosis (PMID: 12843338, 23379534). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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: 99896). -

Retinitis pigmentosa 12 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;D;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.6	.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.7	D;.;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D;.;D;D;D
Sift4G	Uncertain	0.053	T;.;D;D;D
Polyphen		0.93	P;.;P;P;.
Vest4		0.87
MutPred		0.64		.;Loss of stability (P = 0.0017);Loss of stability (P = 0.0017);.;.;
MVP		0.93
MPC		0.24
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62635659; hg19: chr1-197404292;