rs773233587

Variant names:

• chr1-197421540-A-C
• rs773233587
• NM_201253.3:c.1712A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_201253.3(CRB1):​c.1712A>C​(p.Glu571Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E571E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 4.77

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 Uncertain_significance. Variant got 2 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, 7 uncertain in NM_201253.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB1	NM_201253.3	c.1712A>C	p.Glu571Ala	missense_variant	Exon 6 of 12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.1712A>C	p.Glu571Ala	missense_variant	Exon 6 of 12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251168 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461892 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

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: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Uncertain:1

Apr 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CRB1 c.1712A>C (p.Glu571Ala) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251168 control chromosomes. c.1712A>C has been reported in the compound heterozygous state together with a pathogenic variant in the literature in at least 2 individuals affected with inherited retinal dystrophies (e.g. Carss_2017, Daich Varela_2023, Rodriguez_2023, Turro_2020). This variant was also found in trans with a pathogenic variant in one individual with macular dystrophy (age of onset unknown), however age-related macular degeneration was not ruled out (Weisschuh_2024). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 36099972, 37762234, 32581362, 37734845). ClinVar contains an entry for this variant (Variation ID: 438071). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Mar 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 571 of the CRB1 protein (p.Glu571Ala). This variant is present in population databases (rs773233587, gnomAD 0.0009%). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 28041643, 32581362). ClinVar contains an entry for this variant (Variation ID: 438071). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T;.;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.4	M;.;M;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.9	D;D;.;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.072	T;T;.;T;T
Sift4G	Benign	0.13	T;T;.;T;T
Polyphen		1.0	.;D;.;D;D
Vest4		0.78
MutPred		0.57		Loss of disorder (P = 0.3129);.;Loss of disorder (P = 0.3129);Loss of disorder (P = 0.3129);.;
MVP		0.89
MPC		0.24
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.26
gMVP		0.66

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: rs773233587; hg19: chr1-197390670;