chr3-150972617-G-A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_174878.3(CLRN1):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CLRN1
NM_174878.3 missense

Scores

1
13
5

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.93
Variant links:
Genes affected
CLRN1 (HGNC:12605): (clarin 1) This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
SIAH2-AS1 (HGNC:40526): (SIAH2 antisense RNA 1)
CLRN1-AS1 (HGNC:30895): (CLRN1 antisense RNA 1)

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1
In a chain Clarin-1 (size 231) in uniprot entity CLRN1_HUMAN there are 47 pathogenic changes around while only 2 benign (96%) in NM_174878.3
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-150972617-G-A is Pathogenic according to our data. Variant chr3-150972617-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-150972617-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLRN1NM_174878.3 linkc.92C>T p.Pro31Leu missense_variant Exon 1 of 3 ENST00000327047.6 NP_777367.1 P58418-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLRN1ENST00000327047.6 linkc.92C>T p.Pro31Leu missense_variant Exon 1 of 3 1 NM_174878.3 ENSP00000322280.1 P58418-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 61 Pathogenic:1
Jul 01, 2011
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

not provided Pathogenic:1
Apr 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CLRN1 protein (p.Pro31Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 21310491). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30575). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLRN1 function (PMID: 21310491). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1
Oct 24, 2018
Blueprint Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Uncertain
0.099
D
MetaRNN
Uncertain
0.72
D;D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
1.4
L;L;.
PhyloP100
2.9
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.2
D;D;.
REVEL
Uncertain
0.51
Sift
Uncertain
0.0060
D;D;.
Sift4G
Benign
0.10
T;T;.
Polyphen
0.99
D;.;.
Vest4
0.43
MutPred
0.55
Gain of catalytic residue at P31 (P = 0.0055);Gain of catalytic residue at P31 (P = 0.0055);.;
MVP
0.88
MPC
0.14
ClinPred
0.99
D
GERP RS
4.4
PromoterAI
0.0062
Neutral
Varity_R
0.19
gMVP
0.58
Mutation Taster
=10/90
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs374390376; hg19: chr3-150690404; API