The IQCB1 c.424_425delTT (p.Phe142ProfsTer5) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Phe142ProfsTer5 variant has been reported in three studies in which it is found in a total of nine individuals with Senior Loken syndrome, including in seven patients in a homozygous state and in two patients in a compound heterozygous state who both carried a null variant on the second allele (Otto et al. 2005; Estrada-Cuzcano et al. 2011; Halbritter et al. 2013). The p.Phe142ProfsTer5 variant was absent from 347 control subjects but is reported at a frequency of 0.00023 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Phe142ProfsTer5 variant is classified as pathogenic for Senior Loken syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_001023570.4(IQCB1):c.424_425del (p.Phe142fs)
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.
(12)
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
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001023570.4(IQCB1):c.424_425del (p.Phe142fs)
Variation ID: 1831 Accession: VCV000001831.47
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 3q13.33 3: 121808978-121808979 (GRCh38) [ NCBI UCSC ] 3: 121527825-121527826 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 20, 2024 Mar 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001023570.4:c.424_425del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018864.2:p.Phe142fs frameshift NM_001023570.2:c.424_425del NM_001023571.4:c.424_425del NP_001018865.2:p.Phe142fs frameshift NM_001319107.2:c.424_425del NP_001306036.1:p.Phe142fs frameshift NR_134968.2:n.619_620del non-coding transcript variant NC_000003.12:g.121808981_121808982del NC_000003.11:g.121527828_121527829del NG_015887.1:g.31101_31102del - Protein change
- F142fs
- Other names
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- Canonical SPDI
- NC_000003.12:121808977:AAAAA:AAA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
- Comment on variant
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. |
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| 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 (6) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000001905.15 | |
| Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2015 | RCV000505085.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2023 | RCV000822567.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 23, 2021 | RCV001093170.29 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 6, 2017 | RCV001073766.3 |
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. |
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Pathogenic
(Dec 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239326.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Jun 17, 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: SCV001762005.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Rod-cone dystrophy (present) , Keratoconus (present)
Sex: male
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Pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Senior-Loken syndrome 5
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915984.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The IQCB1 c.424_425delTT (p.Phe142ProfsTer5) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Phe142ProfsTer5 variant has been … (more)
The IQCB1 c.424_425delTT (p.Phe142ProfsTer5) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Phe142ProfsTer5 variant has been reported in three studies in which it is found in a total of nine individuals with Senior Loken syndrome, including in seven patients in a homozygous state and in two patients in a compound heterozygous state who both carried a null variant on the second allele (Otto et al. 2005; Estrada-Cuzcano et al. 2011; Halbritter et al. 2013). The p.Phe142ProfsTer5 variant was absent from 347 control subjects but is reported at a frequency of 0.00023 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Phe142ProfsTer5 variant is classified as pathogenic for Senior Loken syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Senior-Loken syndrome 5
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573560.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The IQCB1 c.424_425del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The IQCB1 c.424_425del 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. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Senior-Loken syndrome 5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813901.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001824779.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23446637, 21866095, 15723066, 28832562, 20881296, 29453417, 31980526, 32581362) (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephronophthisis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000963376.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe142Profs*5) in the IQCB1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Phe142Profs*5) 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). This variant is present in population databases (rs750962965, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis and Senior-L√∏ken syndrome (PMID: 15723066, 20881296, 21866095, 23188109, 24625443, 28041643, 28832562). This variant is also known as c.224_225delTT, p.F142fsX146. ClinVar contains an entry for this variant (Variation ID: 1831). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Senior-Loken syndrome 5
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004192436.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250020.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598854.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
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Pathogenic
(Sep 01, 2016)
|
no assertion criteria provided
Method: clinical testing
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Senior-Loken syndrome 5
Affected status: yes
Allele origin:
inherited
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804661.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 11, 2011)
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no assertion criteria provided
Method: literature only
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SENIOR-LOKEN SYNDROME 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022063.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 19, 2015 |
Comment on evidence:
In affected members of 2 German families and 2 Swiss families with Senior-Loken syndrome-5 (SLSN5; 609254), Otto et al. (2005) identified a homozygous 2-bp deletion … (more)
In affected members of 2 German families and 2 Swiss families with Senior-Loken syndrome-5 (SLSN5; 609254), Otto et al. (2005) identified a homozygous 2-bp deletion (TT) at nucleotide 424 in exon 6 of the IQCB1 gene, resulting in a frameshift and premature termination. In a woman with Leber congenital amaurosis (LCA), Estrada-Cuzcano et al. (2011) identified homozygosity for the 424delTT mutation in the IQCB1 gene. At 34 years of age, she retained normal kidney function. (less)
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Comment:
Comment:
The IQCB1 c.424_425del 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. Based on this evidence we have classified this variant as Pathogenic.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23446637, 21866095, 15723066, 28832562, 20881296, 29453417, 31980526, 32581362)
Comment:
This sequence change creates a premature translational stop signal (p.Phe142Profs*5) 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). This variant is present in population databases (rs750962965, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis and Senior-L√∏ken syndrome (PMID: 15723066, 20881296, 21866095, 23188109, 24625443, 28041643, 28832562). This variant is also known as c.224_225delTT, p.F142fsX146. ClinVar contains an entry for this variant (Variation ID: 1831). For these reasons, this variant has been classified as Pathogenic.
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:
The IQCB1 c.424_425delTT (p.Phe142ProfsTer5) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Phe142ProfsTer5 variant has been reported in three studies in which it is found in a total of nine individuals with Senior Loken syndrome, including in seven patients in a homozygous state and in two patients in a compound heterozygous state who both carried a null variant on the second allele (Otto et al. 2005; Estrada-Cuzcano et al. 2011; Halbritter et al. 2013). The p.Phe142ProfsTer5 variant was absent from 347 control subjects but is reported at a frequency of 0.00023 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Phe142ProfsTer5 variant is classified as pathogenic for Senior Loken syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The IQCB1 c.424_425del 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. Based on this evidence we have classified this variant as Pathogenic.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23446637, 21866095, 15723066, 28832562, 20881296, 29453417, 31980526, 32581362)
Comment:
This sequence change creates a premature translational stop signal (p.Phe142Profs*5) 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). This variant is present in population databases (rs750962965, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis and Senior-L√∏ken syndrome (PMID: 15723066, 20881296, 21866095, 23188109, 24625443, 28041643, 28832562). This variant is also known as c.224_225delTT, p.F142fsX146. ClinVar contains an entry for this variant (Variation ID: 1831). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data. | Stark Z | European journal of human genetics : EJHG | 2017 | PMID: 28832562 |
| 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 |
| Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy. | Coppieters F | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24625443 |
| 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 |
| High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing. | Halbritter J | Journal of medical genetics | 2012 | PMID: 23188109 |
| Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. | Wang X | Human mutation | 2011 | PMID: 21901789 |
| Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. | Chaki M | Kidney international | 2011 | PMID: 21866095 |
| IQCB1 mutations in patients with leber congenital amaurosis. | Estrada-Cuzcano A | Investigative ophthalmology & visual science | 2011 | PMID: 20881296 |
| 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 rs750962965 ...
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.
NCBI staff reviewed the sequence information reported in PubMed 15723066 Fig. 2b to determine the location of this allele on the current reference sequence.