For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30778). This variant is also known as c.1381C>T, Arg461*. This premature translational stop signal has been observed in individual(s) with autosomal recessive Leber congenital amaurosis and early onset retinitis pigmentosa (PMID: 18076122, 20881296, 21220633, 23847139, 24066033, 29053603). This variant is present in population databases (rs373909351, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg489*) in the IQCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQCB1 are known to be pathogenic (PMID: 15723066, 21901789, 23559409, 28041643).
ClinVar Genomic variation as it relates to human health
NM_001023570.4(IQCB1):c.1465C>T (p.Arg489Ter)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001023570.4(IQCB1):c.1465C>T (p.Arg489Ter)
Variation ID: 30778 Accession: VCV000030778.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q13.33 3: 121772659 (GRCh38) [ NCBI UCSC ] 3: 121491506 (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 Oct 19, 2015 Jun 17, 2024 Feb 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001023570.4:c.1465C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018864.2:p.Arg489Ter nonsense NM_001023571.4:c.1066C>T NP_001018865.2:p.Arg356Ter nonsense NM_001319107.2:c.1465C>T NP_001306036.1:p.Arg489Ter nonsense NR_134968.2:n.1550C>T non-coding transcript variant NC_000003.12:g.121772659G>A NC_000003.11:g.121491506G>A NG_015887.1:g.67421C>T - Protein change
- R489*, R356*
- Other names
- -
- Canonical SPDI
- NC_000003.12:121772658:G:A
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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. |
|||
| IQCB1 | - | - |
GRCh38 GRCh37 |
525 | 546 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 8, 2024 | RCV000023757.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 8, 2023 | RCV000800060.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 24, 2017 | RCV001075299.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Nephronophthisis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000939758.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30778). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30778). This variant is also known as c.1381C>T, Arg461*. This premature translational stop signal has been observed in individual(s) with autosomal recessive Leber congenital amaurosis and early onset retinitis pigmentosa (PMID: 18076122, 20881296, 21220633, 23847139, 24066033, 29053603). This variant is present in population databases (rs373909351, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg489*) in the IQCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQCB1 are known to be pathogenic (PMID: 15723066, 21901789, 23559409, 28041643). (less)
|
|
|
Pathogenic
(May 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Senior-Loken syndrome 5
The diagnosis of Senior-Loken
(more...)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746674.1 First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
Comment:
The maternally-inherited c.1465C>T is a nonsense variant, which is predicted to result in loss of function in the IQCB1 gene where loss of function is … (more)
The maternally-inherited c.1465C>T is a nonsense variant, which is predicted to result in loss of function in the IQCB1 gene where loss of function is a known mechanism of Senior-Loken syndrome 5, MIM 609254. The c.1465C>T variant was observed to be in trans with a c.1518_1519delCA pathogenic variant based on segregation analysis in the family. Both variants are also also present in the patient's similarly affected sister. (less)
Number of individuals with the variant: 2
Clinical Features:
Stage 5 chronic kidney disease (present) , Large central visual field defect (present) , Hyperpigmented nevi (present) , Abnormal retinal morphology (present)
Family history: yes
Age: 26-32 years
Sex: male
Ethnicity/Population group: White
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2017-05-23
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(Nov 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001240916.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(Feb 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Senior-Loken syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001523521.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Senior-Loken syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136569.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(Nov 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Senior-Loken syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV001752509.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 01, 2011)
|
no assertion criteria provided
Method: literature only
|
SENIOR-LOKEN SYNDROME 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045048.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 19, 2015 |
Comment on evidence:
For discussion of the arg489-to-ter (R489X) mutation in the IQCB1 gene that was found in compound heterozygous state in patients with Senior-Loken syndrome (SLSN5; 609254) … (more)
For discussion of the arg489-to-ter (R489X) mutation in the IQCB1 gene that was found in compound heterozygous state in patients with Senior-Loken syndrome (SLSN5; 609254) by Stone et al. (2011), see 609237.0001 and 609237.0007. (less)
|
Comment:
Comment:
The maternally-inherited c.1465C>T is a nonsense variant, which is predicted to result in loss of function in the IQCB1 gene where loss of function is a known mechanism of Senior-Loken syndrome 5, MIM 609254. The c.1465C>T variant was observed to be in trans with a c.1518_1519delCA pathogenic variant based on segregation analysis in the family. Both variants are also also present in the patient's similarly affected sister.
Comment on condition
The diagnosis of Senior-Loken syndrome, type 5, explains this individual;s visual and kidney problems. However, it does not explain his numerous melanotic nevi.
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. |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30778). This variant is also known as c.1381C>T, Arg461*. This premature translational stop signal has been observed in individual(s) with autosomal recessive Leber congenital amaurosis and early onset retinitis pigmentosa (PMID: 18076122, 20881296, 21220633, 23847139, 24066033, 29053603). This variant is present in population databases (rs373909351, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg489*) in the IQCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQCB1 are known to be pathogenic (PMID: 15723066, 21901789, 23559409, 28041643).
Comment:
The maternally-inherited c.1465C>T is a nonsense variant, which is predicted to result in loss of function in the IQCB1 gene where loss of function is a known mechanism of Senior-Loken syndrome 5, MIM 609254. The c.1465C>T variant was observed to be in trans with a c.1518_1519delCA pathogenic variant based on segregation analysis in the family. Both variants are also also present in the patient's similarly affected sister.
Comment on condition
The diagnosis of Senior-Loken syndrome, type 5, explains this individual;s visual and kidney problems. However, it does not explain his numerous melanotic nevi.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies. | Di Iorio V | Genes | 2017 | PMID: 29053603 |
| Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. | Carss KJ | American journal of human genetics | 2017 | PMID: 28041643 |
| Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients. | Verma A | PloS one | 2013 | PMID: 24066033 |
| Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. | Wang X | Journal of medical genetics | 2013 | PMID: 23847139 |
| Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. | Halbritter J | Human genetics | 2013 | PMID: 23559409 |
| Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. | Wang X | Human mutation | 2011 | PMID: 21901789 |
| Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome. | Stone EM | Archives of ophthalmology (Chicago, Ill. : 1960) | 2011 | PMID: 21220633 |
| IQCB1 mutations in patients with leber congenital amaurosis. | Estrada-Cuzcano A | Investigative ophthalmology & visual science | 2011 | PMID: 20881296 |
| Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing. | Otto EA | Human mutation | 2008 | PMID: 18076122 |
| Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. | Otto EA | Nature genetics | 2005 | PMID: 15723066 |
Text-mined citations for rs373909351 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.