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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 2022
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:: RCV001376502.2

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]

Observations:

Condition(s)

Name:: Usher syndrome type 3A
Synonyms:: USHER SYNDROME, TYPE IIIA
Identifiers:: MONDO: MONDO:0010170; MedGen: C5779850; OMIM: 276902

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001573675	Ocular Genomics Institute, Massachusetts Eye and Ear	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 8, 2021)	germline	research	PubMed (6) [See all records that cite these PMIDs] 28041643, 24596593, 23304067, 15521980, 12080385, 25741868
SCV002058400	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:12080385

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001573675

Ocular Genomics Institute, Massachusetts Eye and Ear

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 8, 2021)

germline

research

PubMed (6)
[See all records that cite these PMIDs]

SCV002058400

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

PMID:12080385

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	research, clinical testing

Citations

PubMed

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

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 (6)

Details of each submission

From Ocular Genomics Institute, Massachusetts Eye and Ear, SCV001573675.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (6)

Description

The CLRN1 c.189C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic.

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

From 3billion, SCV002058400.1

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

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004397, PMID:12080385). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000014, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Jun 17, 2024

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