rs397517932

Positions:

• chr3-150941709-AATGAC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_174878.3(CLRN1):​c.301_305delGTCAT​(p.Val101fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLRN1 NM_174878.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.81

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-150941709-AATGAC-A is Pathogenic according to our data. Variant chr3-150941709-AATGAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-150941709-AATGAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.301_305delGTCAT	p.Val101fs	frameshift_variant	2/3	ENST00000327047.6	NP_777367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.301_305delGTCAT	p.Val101fs	frameshift_variant	2/3	1	NM_174878.3	ENSP00000322280.1
ENSG00000260234	ENST00000569170.5	n.28_32delGTCAT		non_coding_transcript_exon_variant	1/11	1		ENSP00000457784.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251374 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135854

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461766 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change creates a premature translational stop signal (p.Val101Serfs*27) 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 (rs397517932, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 21675857). ClinVar contains an entry for this variant (Variation ID: 48145). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CLRN1: PVS1, PP1:Strong, PM2, PM3 -

Usher syndrome type 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Dec 02, 2014

- -

Usher syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Faculty of Health Sciences, Beirut Arab University

Feb 12, 2022

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 08, 2011

The Val101fs variant in CLRN1 has been identified in the homozygous state in two Lebanese siblings with Usher syndrome (Akoury 2011). This variant results in a frameshift at position 101 leading to a premature stop 27 codons downstream, whi ch is predicted to lead to a truncated or absent protein. In summary, this varia nt meets our criteria to be classified as pathogenic. -

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: rs397517932; hg19: chr3-150659496;