ClinVar Genomic variation as it relates to human health
NM_014714.4(IFT140):c.2399+1G>T
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014714.4(IFT140):c.2399+1G>T
Variation ID: 31680 Accession: VCV000031680.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 1557934 (GRCh38) [ NCBI UCSC ] 16: 1607935 (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 Dec 15, 2018 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014714.4:c.2399+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000016.10:g.1557934C>A NC_000016.9:g.1607935C>A NG_032783.1:g.59175G>T - Protein change
- Other names
- IVS19DS, G-T, +1
- Canonical SPDI
- NC_000016.10:1557933:C:A
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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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
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HI score
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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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IFT140 | - | - |
GRCh38 GRCh37 |
1045 | 1883 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000024360.16 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 11, 2021 | RCV000515584.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2017 | RCV001075306.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2022 | RCV001536095.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2021 | RCV001818178.6 | |
IFT140-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2023 | RCV003924859.1 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV003993751.1 |
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. |
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Pathogenic
(Dec 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240924.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Jun 15, 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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Genetic Services Laboratory, University of Chicago
Accession: SCV002064445.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the IFT140 gene demonstrated a sequence change in the canonical splice donor site of intron 19, c.2399+1G>T. This sequence change is … (more)
DNA sequence analysis of the IFT140 gene demonstrated a sequence change in the canonical splice donor site of intron 19, c.2399+1G>T. This sequence change is predicted to affect mRNA splicing and is likely to result in an absent or truncated protein. It has been described in the gnomAD database in the non-Finnish European subpopulation with a low frequency of 0.012% only (dbSNP rs376586707). This sequence change has been previously described in the compound heterozygous state in family and individuals with IFT140-related disorders (PMIDs: 22503633, 26968735, 23418020). Collectively, this evidence indicates that the c.2399+1G>T change is pathogenic. (less)
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Pathogenic
(Nov 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 80
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581771.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM2_SUP, PP1
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Number of individuals with the variant: 3
Sex: female
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Pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Saldino-Mainzer syndrome
Retinitis pigmentosa 80
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752805.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Saldino-Mainzer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001200458.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 19 of the IFT140 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 19 of the IFT140 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). This variant is present in population databases (rs376586707, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with IFT140-related conditions (PMID: 22503633, 23418020, 26968735). ClinVar contains an entry for this variant (Variation ID: 31680). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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IFT140-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004738355.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The IFT140 c.2399+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant along with another IFT140 variant has … (more)
The IFT140 c.2399+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant along with another IFT140 variant has been reported to be causative for Mainzer-Saldino syndrome and Jeune syndrome (Perrault et al. 2012. PubMed ID: 22503633; Schmidts et al. 2013. PubMed ID: 23418020). It has also been reported along with a missense IFT140 variant in two siblings with retinal dystrophy (Hull et al. 2016. PubMed ID: 26968735). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt consensus splice donor sites in IFT140 are expected to be pathogenic. Of note, monoallelic IFT140 loss-of-function pathogenic variants have been reported to cause the autosomal dominant polycystic kidney-spectrum phenotype and this splicing variant is among the pathogenic changes found in this study (Senum et al. 2022. PubMed ID: 34890546). This variant is interpreted as pathogenic for both autosomal recessive and autosomal dominant IFT140-related disorders. (less)
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Pathogenic
(Oct 29, 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: SCV002504221.2
First in ClinVar: Apr 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed with a second variant on the opposite allele … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed with a second variant on the opposite allele (in trans) in patients with Mainzer-Saldino syndrome or isolated retinal dystrophy in the published literature (Schmidts et al., 2013; Hull et al., 2016); This variant is associated with the following publications: (PMID: 31397098, 26968735, 28724397, 22503633, 29688594, 31980526, 31589614, 32037395, 23418020) (less)
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Pathogenic
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant polycystic kidney disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812569.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in IFT140 occurs within the canonical splice donor site of intron 19. It is predicted to cause native donor site loss and … (more)
This sequence change in IFT140 occurs within the canonical splice donor site of intron 19. It is predicted to cause native donor site loss and cryptic donor creation leading to a one bp deletion resulting in a frameshift (exon 19/31) leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 22282595, 34890546). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.04% (463/1,179,776 alleles) in the European (non-Finnish) population. This variant has been reported as a common cause of IFT140-related polycystic kidney disease (PKD) with a distinctive monoallelic phenotype of mild PKD with large cysts, limited kidney insufficiency, and few liver cysts (PMID: 34890546). The variant has been reported to segregate with PKD in multiple families (PMID: 34890546). This variant has been detected as compound heterozygous with a second pathogenic variant in at least two individuals with a ciliopathy phenotype (PMID: 22503633). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM3. (less)
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Pathogenic
(May 01, 2013)
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no assertion criteria provided
Method: literature only
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SHORT-RIB THORACIC DYSPLASIA 9 WITHOUT POLYDACTYLY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045653.8
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
Short-Rib Thoracic Dysplasia 9 In an 18-month-old boy with short-rib thoracic dysplasia-9 (SRDT9; 266920), who had a clinical diagnosis of Jeune syndrome, Perrault et al. … (more)
Short-Rib Thoracic Dysplasia 9 In an 18-month-old boy with short-rib thoracic dysplasia-9 (SRDT9; 266920), who had a clinical diagnosis of Jeune syndrome, Perrault et al. (2012) identified compound heterozygosity for a c.2399+1G-T transversion in intron 19 of the IFT140 gene, and a missense mutation (G212R; 614620.0005). The patient was hypotonic with poor feeding at birth and exhibited developmental delay, short thorax with short ribs, trident-shaped spurs on long bones, cone-shaped epiphyses of the phalanges, and increased echogenicity of the kidneys with nonspecific tubulointerstitial nephritis. For discussion of the c.2399+1G-T mutation that Perrault et al. (2012) identified in compound heterozygous state in a 17-year-old boy with SRDT9, who had a clinical diagnosis of Mainzer-Saldino syndrome, see 614620.0001. In a 39-year-old Austrian woman with a clinical diagnosis of Mainzer-Saldino syndrome, who had a small thorax, brachymesophalangism, and cone-shaped epiphyses, with childhood onset of retinal pigmentary dystrophy and small cystic kidneys resulting in end-stage renal disease by 12 years of age, Schmidts et al. (2013) identified compound heterozygosity for the c.2399+1G-T splice site mutation in the IFT140 gene and a c.4078T-C transition resulting in a cys1360-to-arg (C1360R; 614620.0007) substitution at a highly conserved residue. Retinitis Pigmentosa 80 In a 67-year-old Caucasian British man (patient 2) with retinitis pigmentosa (RP80; 617781), who also had hearing loss but was negative for mutation in 9 Usher syndrome (see 276900)-associated genes, Hull et al. (2016) identified compound heterozygosity for the c.2399+1G-T splice site mutation (c.2399+1G-T, NM_014714.3) and a c.2815T-C transition in the IFT140 gene, resulting in a ser939-to-pro (S939P; 614620.0015) substitution. The proband's younger sister, who had RP without hearing loss, was also compound heterozygous for the IFT140 variants, whereas his unaffected son carried only one of the mutations. Both patients exhibited normal development without skeletal manifestations or renal failure. Transient transfection in hTERT-RPE1 cells followed by immunostaining demonstrated significantly reduced basal body localization with the S939P mutant compared to wildtype. (less)
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Pathogenic
(May 01, 2013)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 80
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000611640.5
First in ClinVar: Nov 26, 2017 Last updated: Mar 10, 2024 |
Comment on evidence:
Short-Rib Thoracic Dysplasia 9 In an 18-month-old boy with short-rib thoracic dysplasia-9 (SRDT9; 266920), who had a clinical diagnosis of Jeune syndrome, Perrault et al. … (more)
Short-Rib Thoracic Dysplasia 9 In an 18-month-old boy with short-rib thoracic dysplasia-9 (SRDT9; 266920), who had a clinical diagnosis of Jeune syndrome, Perrault et al. (2012) identified compound heterozygosity for a c.2399+1G-T transversion in intron 19 of the IFT140 gene, and a missense mutation (G212R; 614620.0005). The patient was hypotonic with poor feeding at birth and exhibited developmental delay, short thorax with short ribs, trident-shaped spurs on long bones, cone-shaped epiphyses of the phalanges, and increased echogenicity of the kidneys with nonspecific tubulointerstitial nephritis. For discussion of the c.2399+1G-T mutation that Perrault et al. (2012) identified in compound heterozygous state in a 17-year-old boy with SRDT9, who had a clinical diagnosis of Mainzer-Saldino syndrome, see 614620.0001. In a 39-year-old Austrian woman with a clinical diagnosis of Mainzer-Saldino syndrome, who had a small thorax, brachymesophalangism, and cone-shaped epiphyses, with childhood onset of retinal pigmentary dystrophy and small cystic kidneys resulting in end-stage renal disease by 12 years of age, Schmidts et al. (2013) identified compound heterozygosity for the c.2399+1G-T splice site mutation in the IFT140 gene and a c.4078T-C transition resulting in a cys1360-to-arg (C1360R; 614620.0007) substitution at a highly conserved residue. Retinitis Pigmentosa 80 In a 67-year-old Caucasian British man (patient 2) with retinitis pigmentosa (RP80; 617781), who also had hearing loss but was negative for mutation in 9 Usher syndrome (see 276900)-associated genes, Hull et al. (2016) identified compound heterozygosity for the c.2399+1G-T splice site mutation (c.2399+1G-T, NM_014714.3) and a c.2815T-C transition in the IFT140 gene, resulting in a ser939-to-pro (S939P; 614620.0015) substitution. The proband's younger sister, who had RP without hearing loss, was also compound heterozygous for the IFT140 variants, whereas his unaffected son carried only one of the mutations. Both patients exhibited normal development without skeletal manifestations or renal failure. Transient transfection in hTERT-RPE1 cells followed by immunostaining demonstrated significantly reduced basal body localization with the S939P mutant compared to wildtype. (less)
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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 |
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Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype. | Senum SR | American journal of human genetics | 2022 | PMID: 34890546 |
Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140. | Hull S | Investigative ophthalmology & visual science | 2016 | PMID: 26968735 |
Mutations in human IFT140 cause non-syndromic retinal degeneration. | Xu M | Human genetics | 2015 | PMID: 26216056 |
Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome. | Miller KA | PLoS genetics | 2013 | PMID: 24009529 |
Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease. | Schmidts M | Human mutation | 2013 | PMID: 23418020 |
Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. | Perrault I | American journal of human genetics | 2012 | PMID: 22503633 |
Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation. | Jonassen JA | Journal of the American Society of Nephrology : JASN | 2012 | PMID: 22282595 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs376586707 ...
HelpRecord last updated May 19, 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.