NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter) AND Usher syndrome type 3

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 7, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004647.8

Allele description [Variation Report for NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)]

NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)

Gene:

CLRN1:clarin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q25.1

Genomic location:

Preferred name:

NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)

HGVS:

NC_000003.12:g.150972520G>T
NG_009168.1:g.5480C>A
NM_001195794.1:c.189C>A
NM_001256819.2:c.189C>A
NM_174878.3:c.189C>AMANE SELECT
NP_001182723.1:p.Tyr63Ter
NP_001243748.1:p.Tyr63Ter
NP_777367.1:p.Tyr63Ter
LRG_700t1:c.189C>A
LRG_700:g.5480C>A
LRG_700p1:p.Tyr63Ter
NC_000003.11:g.150690307G>T
NM_174878.3:c.189C>A
NR_046380.3:n.208C>A
c.189C>A
p.Tyr63X

Protein change:

Y63*; TYR63TER

Links:

OMIM: 606397.0006; dbSNP: rs111033267

NCBI 1000 Genomes Browser:

rs111033267

Molecular consequence:

NR_046380.3:n.208C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001195794.1:c.189C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001256819.2:c.189C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_174878.3:c.189C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Usher syndrome type 3
Synonyms:: Usher Syndrome, Type III
Identifiers:: MONDO: MONDO:0016485; MedGen: C1568248

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024821	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2004)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15521980, 12080385
SCV000486175	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Apr 12, 2016)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24596593, 12080385, 23304067 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000919233	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 7, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23304067, 12080385 Citation Link,
SCV002081535	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 11, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability.

Aller E, Jaijo T, Oltra S, Alió J, Galán F, Nájera C, Beneyto M, Millán JM.

Clin Genet. 2004 Dec;66(6):525-9.

PubMed [citation]

PMID:: 15521980

Strategies for genetic study of hearing loss in the Brazilian northeastern region.

Melo US, Santos S, Cavalcanti HG, Andrade WT, Dantas VG, Rosa MR, Mingroni-Netto RC.

Int J Mol Epidemiol Genet. 2014;5(1):11-21.

PubMed [citation]

PMID:: 24596593
PMCID:: PMC3939003

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024821.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 3 sibs with Usher syndrome type IIIA (USH3A; 276902) from a nonconsanguineous Spanish family, Adato et al. (2002) detected a 189C-A substitution in the CLRN1 gene, which was expected to cause a tyr63-to-ter (Y63X) homozygous nonsense mutation.

Aller et al. (2004) stated that the family with the Y63X mutation reported by Adato et al. (2002) could be diagnosed clinically with Usher syndrome type I because hearing impairment was profound and stable. Aller et al. (2004) considered that progressive hearing loss is not the definitive parameter in distinguishing Usher syndrome type III from Usher syndrome types I and II.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000486175.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919233.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CLRN1 c.189C>A (p.Tyr63X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.8e-05 in 277198 control chromosomes. c.189C>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Usher Syndrome Type 3 (Adato_2002; Garcia-Garcia_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002081535.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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