rs121908143

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000327047.6(CLRN1):c.118T>G(p.Cys40Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,614,146 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 (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CLRN1
ENST00000327047.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:3

Conservation

PhyloP100: 8.71

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]

CLRN1 links:

(HGNC:):

links:

CLRN1-AS1 (HGNC:30895): (CLRN1 antisense RNA 1)

CLRN1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Clarin-1 (size 231) in uniprot entity CLRN1_HUMAN there are 44 pathogenic changes around while only 2 benign (96%) in ENST00000327047.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 3-150972591-A-C is Pathogenic according to our data. Variant chr3-150972591-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-150972591-A-C is described in Lovd as [Likely_pathogenic]. Variant chr3-150972591-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLRN1	NM_174878.3 linkuse as main transcript	c.118T>G	p.Cys40Gly	missense_variant	1/3	ENST00000327047.6	NP_777367.1
CLRN1	NM_001195794.1 linkuse as main transcript	c.118T>G	p.Cys40Gly	missense_variant	1/4		NP_001182723.1
CLRN1	NM_001256819.2 linkuse as main transcript	c.118T>G	p.Cys40Gly	missense_variant	1/4		NP_001243748.1
CLRN1	NR_046380.3 linkuse as main transcript	n.137T>G		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6 linkuse as main transcript	c.118T>G	p.Cys40Gly	missense_variant	1/3	1	NM_174878.3	ENSP00000322280	P1	P58418-3
	ENST00000469268.1 linkuse as main transcript	n.236-28983A>C		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5 linkuse as main transcript	n.124-90335A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251462

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135902

show subpopulations

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:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

113

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000210

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000654

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 40 of the CLRN1 protein (p.Cys40Gly). This variant is present in population databases (rs121908143, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 15521980; Invitae). ClinVar contains an entry for this variant (Variation ID: 4399). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25743179, 23304067, 21310491, 15521980, 19753315, 29545425, 31963381, 29331482) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2015	- -

Usher syndrome type 3

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Apr 19, 2017	- -

Usher syndrome type 3A

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 09, 2019	- -

CLRN1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

The CLRN1 c.118T>G variant is predicted to result in the amino acid substitution p.Cys40Gly. This variant has been reported in the homozygous and compound heterozygous states in multiple patients with Usher syndrome or retinitis pigmentosa (Aller et al. 2004. PubMed ID: 15521980; Guimaraes et al. 2023. PubMed ID: 36162969; Whelan et al. 2020. PubMed ID: 31963381; Table S1, Weisschuh et al. 2024. PubMed ID: 37734845; Table S4, Haer-Wigman et al. 2017. PubMed ID: 28224992). A functional study that injected AAV2 vectors with the variant into the eyes of mice showed that the expression of mutant proteins led to dramatic loss in both retinal function and photoreceptors (Bolch et al. 2018. ARVO Meeting Abstract). This variant is reported in 0.016% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been interpreted as likely pathogenic and pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4399/). This variant is interpreted as likely pathogenic. -

Usher syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 14, 2022

Variant summary: CLRN1 c.118T>G (p.Cys40Gly) results in a non-conservative amino acid change in 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 8e-05 in 251462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CLRN1 causing Usher Syndrome (8e-05 vs 0.0014), allowing no conclusion about variant significance. c.118T>G has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with features of Usher Syndrome type 3 and as a heterozygous genotype in one case report with Unilateral retinitis pigmentosa (RP) (example, Aller_2004, Haer-Wigman_2017, Yong Sim_2018, Whelan_2020, Jiman_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP/P, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Retinitis pigmentosa 61

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Blueprint Genetics

Apr 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T;T

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.4

M;M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.6

D;D;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.96

MVP

0.77

MPC

0.19

ClinPred

0.92

GERP RS

5.3

Varity_R

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over