ClinVar Genomic variation as it relates to human health
NM_174878.3(CLRN1):c.118T>G (p.Cys40Gly)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Likely pathogenic(4); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_174878.3(CLRN1):c.118T>G (p.Cys40Gly)
Variation ID: 4399 Accession: VCV000004399.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q25.1 3: 150972591 (GRCh38) [ NCBI UCSC ] 3: 150690378 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 Dec 30, 2023 Oct 14, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_174878.3:c.118T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777367.1:p.Cys40Gly missense NM_001195794.1:c.118T>G NP_001182723.1:p.Cys40Gly missense NM_001256819.2:c.118T>G NP_001243748.1:p.Cys40Gly missense NR_046380.3:n.137T>G non-coding transcript variant NC_000003.12:g.150972591A>C NC_000003.11:g.150690378A>C NG_009168.1:g.5409T>G LRG_700:g.5409T>G LRG_700t1:c.118T>G LRG_700p1:p.Cys40Gly P58418:p.Cys40Gly - Protein change
- C40G
- Other names
- -
- Canonical SPDI
- NC_000003.12:150972590:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
CLRN1 | - | - |
GRCh38 GRCh37 |
360 | 410 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Feb 1, 2019 | RCV000004649.8 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Dec 7, 2022 | RCV000414238.13 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 11, 2018 | RCV001075346.1 | |
Likely pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001273484.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 14, 2022 | RCV002468960.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 14, 2023 | RCV003466815.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905531.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Hearing abnormality (present) , Hearing impairment (present) , Sensorineural hearing loss disorder (present) , Rod-cone dystrophy (present) , Cone-rod dystrophy (present)
Sex: female
|
|
Likely pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490476.4
First in ClinVar: Jan 09, 2017 Last updated: Dec 17, 2022 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25743179, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25743179, 23304067, 21310491, 15521980, 19753315, 29545425, 31963381, 29331482) (less)
|
|
Pathogenic
(Oct 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002163401.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 40 of the CLRN1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 40 of the CLRN1 protein (p.Cys40Gly). This variant is present in population databases (rs121908143, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 15521980; Invitae). ClinVar contains an entry for this variant (Variation ID: 4399). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 61
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004214403.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Uncertain significance
(Apr 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 3A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800518.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
Uncertain significance
(Dec 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000337866.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 3A
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001156372.1
First in ClinVar: Feb 15, 2020 Last updated: Feb 15, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Adult onset sensorineural hearing impairment (present) , Rod-cone dystrophy (present)
Family history: no
|
|
Uncertain significance
(Apr 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001240966.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
|
|
Likely pathogenic
(Nov 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766549.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: CLRN1 c.118T>G (p.Cys40Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CLRN1 c.118T>G (p.Cys40Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CLRN1 causing Usher Syndrome (8e-05 vs 0.0014), allowing no conclusion about variant significance. c.118T>G has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with features of Usher Syndrome type 3 and as a heterozygous genotype in one case report with Unilateral retinitis pigmentosa (RP) (example, Aller_2004, Haer-Wigman_2017, Yong Sim_2018, Whelan_2020, Jiman_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP/P, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
Pathogenic
(Dec 01, 2004)
|
no assertion criteria provided
Method: literature only
|
USHER SYNDROME, TYPE IIIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024823.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2015 |
Comment on evidence:
In a patient with Usher syndrome type IIIA (USH3A; 276902), Aller et al. (2004) identified homozygosity for a 118T-G transversion in the CLRN1 gene, resulting … (more)
In a patient with Usher syndrome type IIIA (USH3A; 276902), Aller et al. (2004) identified homozygosity for a 118T-G transversion in the CLRN1 gene, resulting in a cys40-to-gly (C40G) mutation. Both parents and an unaffected sister were heterozygous for the mutation. (less)
|
|
Uncertain significance
(Sep 01, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Usher syndrome type 3A
Affected status: yes
Allele origin:
inherited
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804616.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Usher syndrome type 3A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001456566.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
click to load more click to collapse |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Retinal Phenotype of Patients with CLRN1-Associated Usher 3A Syndrome in French Light4Deaf Cohort. | Smirnov VM | Investigative ophthalmology & visual science | 2022 | PMID: 35481838 |
Findings from a Genotyping Study of Over 1000 People with Inherited Retinal Disorders in Ireland. | Whelan L | Genes | 2020 | PMID: 31963381 |
Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease. | Jiman OA | European journal of human genetics : EJHG | 2020 | PMID: 31836858 |
Unilateral retinitis pigmentosa occurring in an individual with a mutation in the CLRN1 gene. | Sim PY | BMJ case reports | 2018 | PMID: 29545425 |
Diagnostic exome sequencing in 266 Dutch patients with visual impairment. | Haer-Wigman L | European journal of human genetics : EJHG | 2017 | PMID: 28224992 |
Disease-causing mutations in the CLRN1 gene alter normal CLRN1 protein trafficking to the plasma membrane. | Isosomppi J | Molecular vision | 2009 | PMID: 19753315 |
Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability. | Aller E | Clinical genetics | 2004 | PMID: 15521980 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLRN1 | - | - | - | - |
Text-mined citations for rs121908143 ...
HelpRecord last updated Feb 04, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.