rs786204428

Positions:

• chr3-150972556-CCCTG-CATTGGACA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000327047.6(CLRN1):​c.149_152delinsTGTCCAAT​(p.Ser50LeufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLRN1 ENST00000327047.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.40

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]

(HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-150972557-CCTG-ATTGGACA is Pathogenic according to our data. Variant chr3-150972557-CCTG-ATTGGACA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.149_152delinsTGTCCAAT	p.Ser50LeufsTer12	frameshift_variant	1/3	ENST00000327047.6	NP_777367.1
CLRN1	NM_001195794.1	c.149_152delinsTGTCCAAT	p.Ser50LeufsTer12	frameshift_variant	1/4		NP_001182723.1
CLRN1	NM_001256819.2	c.149_152delinsTGTCCAAT	p.Ser50LeufsTer12	frameshift_variant	1/4		NP_001243748.1
CLRN1	NR_046380.3	n.168_171delinsTGTCCAAT		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.149_152delinsTGTCCAAT	p.Ser50LeufsTer12	frameshift_variant	1/3	1	NM_174878.3	ENSP00000322280	P1
	ENST00000469268.1	n.236-29017_236-29014delinsATTGGACA		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.124-90369_124-90366delinsATTGGACA		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2017	Variant summary: The CLRN1 c.149_152delinsTGTCCAAT (p.Ser50Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent CLRN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant is absent in 122580 control chromosomes while it was reported in several patients with Usher Syndrome in homozygosity or in compound heterozygosity with other pathogenic variant indicating pathogenicity. In addition, multiple clinical diagnostic laboratories classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17893653, 18273898, 12145752, 22135276, 16963483) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	This sequence change creates a premature translational stop signal (p.Ser50Leufs*12) in the CLRN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLRN1 are known to be pathogenic (PMID: 11524702, 24498627). This variant is present in population databases (rs762606406, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 12145752, 22135276). This variant is also known as c.149delCAGGinsTGTCCAAT. ClinVar contains an entry for this variant (Variation ID: 1275768). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa;C3280041:Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

Retinitis pigmentosa 61 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 30, 2017

The p.Ser50fs variant in CLRN1 has been reported in 3 individuals with Usher syn drome type III, who were either homozygous for the variant or compound heterozyg ous for this variant and a second pathogenic variant (Fields 2002 and Le Quesne Stabej 2012). The variant has also been reported in ClinVar by multiple submitte rs as a pathogenic variant (Variation ID: 188726). It has also been identified i n 0.02% (27/126690) of European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs786204428); however this freq uency is low enough to be consistent with a recessive carrier frequency. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CLRN1 gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome type III in an autos omal recessive manner. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204428; hg19: chr3-150690344;