rs374390376

Positions:

• chr3-150972617-G-A
• chr3-150972617-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLRN1 NM_174878.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.93

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain Clarin-1 (size 231) in uniprot entity CLRN1_HUMAN there are 22 pathogenic changes around while only 1 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/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.92C>T	p.Pro31Leu	missense_variant	1/3	ENST00000327047.6	NP_777367.1
CLRN1	NM_001195794.1	c.92C>T	p.Pro31Leu	missense_variant	1/4		NP_001182723.1
CLRN1	NM_001256819.2	c.92C>T	p.Pro31Leu	missense_variant	1/4		NP_001243748.1
CLRN1	NR_046380.3	n.111C>T		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.92C>T	p.Pro31Leu	missense_variant	1/3	1	NM_174878.3	ENSP00000322280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 61 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2011

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2023

ClinVar contains an entry for this variant (Variation ID: 30575). 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. This variant is not present in population databases (gnomAD no frequency). 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). 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLRN1 function (PMID: 21310491). -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 24, 2018

- -

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;.
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
Varity_R		0.19
gMVP		0.58

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: rs374390376; hg19: chr3-150690404;