The INVS c.1453delC (p.Gln485LysfsTer25) variant resulst in a frameshift variant and is predicted to result in premature termination of the protein. The p.Gln485LysfsTer25 variant has been reported in at least three studies in which it is found in a compound heterozygous state in five individuals with early onset nephronophthisis and polycystic kidney disease. All individuals developed end stage renal disease between seven and 36 months of age. (Otto et al. 2003; Tory et al. 2009; Chaki et al. 2011). All individuals carried a null variant on the second allele with three individuals carrying the same stop-gained variant and the remaining two carrying different variants resulting in a frameshift. The p.Gln485LysfsTer25 variant was absent from at least 100 controls and is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Gln485LysfsTer25 variant is classified as pathogenic for nephronophthisis. 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_014425.5(INVS):c.1453del (p.Gln485fs)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_014425.5(INVS):c.1453del (p.Gln485fs)
Variation ID: 11963 Accession: VCV000011963.23
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 9q31.1 9: 100253125 (GRCh38) [ NCBI UCSC ] 9: 103015407 (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 Sep 24, 2016 Oct 8, 2024 Dec 19, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014425.5:c.1453del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055240.2:p.Gln485fs frameshift NM_001318381.2:c.1165del NP_001305310.1:p.Gln389fs frameshift NM_001318382.2:c.475del NP_001305311.1:p.Gln159fs frameshift NM_014425.3:c.1453del NM_014425.4:c.1453delC NR_134606.2:n.1651del non-coding transcript variant NC_000009.12:g.100253125del NC_000009.11:g.103015407del NG_008316.1:g.158897del - Protein change
- Q159fs, Q485fs, Q389fs
- Other names
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p.Gln485Lysfs*25
- Canonical SPDI
- NC_000009.12:100253124:C:
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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.
-
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- 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. |
|||
| INVS | - | - |
GRCh38 GRCh37 |
983 | 1027 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2021 | RCV000012741.37 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2023 | RCV000732404.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2023 | RCV001382990.7 | |
|
INVS-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 3, 2024 | RCV003934826.2 |
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
(Mar 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000860361.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: mixed
|
|
|
Pathogenic
(Sep 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile nephronophthisis
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000916243.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The INVS c.1453delC (p.Gln485LysfsTer25) variant resulst in a frameshift variant and is predicted to result in premature termination of the protein. The p.Gln485LysfsTer25 variant has … (more)
The INVS c.1453delC (p.Gln485LysfsTer25) variant resulst in a frameshift variant and is predicted to result in premature termination of the protein. The p.Gln485LysfsTer25 variant has been reported in at least three studies in which it is found in a compound heterozygous state in five individuals with early onset nephronophthisis and polycystic kidney disease. All individuals developed end stage renal disease between seven and 36 months of age. (Otto et al. 2003; Tory et al. 2009; Chaki et al. 2011). All individuals carried a null variant on the second allele with three individuals carrying the same stop-gained variant and the remaining two carrying different variants resulting in a frameshift. The p.Gln485LysfsTer25 variant was absent from at least 100 controls and is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Gln485LysfsTer25 variant is classified as pathogenic for nephronophthisis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Sep 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile nephronophthisis
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061581.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PVS1, PM2, PM3
|
|
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Pathogenic
(Nov 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile nephronophthisis
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV001752607.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Oct 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002588063.2
First in ClinVar: Nov 05, 2022 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: 12872123, 19177160, 31589614, 21866095) (less)
|
|
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Pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226611.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM2, PM3, PVS1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Nephronophthisis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581981.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln485Lysfs*25) in the INVS gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln485Lysfs*25) in the INVS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in INVS are known to be pathogenic (PMID: 12872123). This variant is present in population databases (rs753348470, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with nephronophthisis (PMID: 12872123, 18076122). ClinVar contains an entry for this variant (Variation ID: 11963). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Apr 01, 2009)
|
no assertion criteria provided
Method: literature only
|
NEPHRONOPHTHISIS 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032976.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 24, 2016 |
Comment on evidence:
For discussion of the 1-bp deletion (1453delC) in exon 10 of the INVS gene that was found in compound heterozygous state in patients with nephronophthisis-2 … (more)
For discussion of the 1-bp deletion (1453delC) in exon 10 of the INVS gene that was found in compound heterozygous state in patients with nephronophthisis-2 (NPHP2; 602088) by Tory et al. (2009), see 243305.0004. (less)
|
|
|
Pathogenic
(Sep 03, 2024)
|
no assertion criteria provided
Method: clinical testing
|
INVS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004754050.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The INVS c.1453delC variant is predicted to result in a frameshift and premature protein termination (p.Gln485Lysfs*25). This variant has been reported in the compound heterozygous … (more)
The INVS c.1453delC variant is predicted to result in a frameshift and premature protein termination (p.Gln485Lysfs*25). This variant has been reported in the compound heterozygous state in multiple individuals with nephronophthisis (See for example, Otto et al 2003. PubMed ID: 12872123; Chaki M et al 2011. PubMed ID: 21866095). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in INVS are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
PVS1, PM2, PM3
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: 12872123, 19177160, 31589614, 21866095)
Comment:
PM2, PM3, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Gln485Lysfs*25) in the INVS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in INVS are known to be pathogenic (PMID: 12872123). This variant is present in population databases (rs753348470, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with nephronophthisis (PMID: 12872123, 18076122). ClinVar contains an entry for this variant (Variation ID: 11963). For these reasons, this variant has been classified as Pathogenic.
Comment:
The INVS c.1453delC variant is predicted to result in a frameshift and premature protein termination (p.Gln485Lysfs*25). This variant has been reported in the compound heterozygous state in multiple individuals with nephronophthisis (See for example, Otto et al 2003. PubMed ID: 12872123; Chaki M et al 2011. PubMed ID: 21866095). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in INVS are expected to be pathogenic. This variant is interpreted 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 INVS c.1453delC (p.Gln485LysfsTer25) variant resulst in a frameshift variant and is predicted to result in premature termination of the protein. The p.Gln485LysfsTer25 variant has been reported in at least three studies in which it is found in a compound heterozygous state in five individuals with early onset nephronophthisis and polycystic kidney disease. All individuals developed end stage renal disease between seven and 36 months of age. (Otto et al. 2003; Tory et al. 2009; Chaki et al. 2011). All individuals carried a null variant on the second allele with three individuals carrying the same stop-gained variant and the remaining two carrying different variants resulting in a frameshift. The p.Gln485LysfsTer25 variant was absent from at least 100 controls and is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Gln485LysfsTer25 variant is classified as pathogenic for nephronophthisis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PVS1, PM2, PM3
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: 12872123, 19177160, 31589614, 21866095)
Comment:
PM2, PM3, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Gln485Lysfs*25) in the INVS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in INVS are known to be pathogenic (PMID: 12872123). This variant is present in population databases (rs753348470, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with nephronophthisis (PMID: 12872123, 18076122). ClinVar contains an entry for this variant (Variation ID: 11963). For these reasons, this variant has been classified as Pathogenic.
Comment:
The INVS c.1453delC variant is predicted to result in a frameshift and premature protein termination (p.Gln485Lysfs*25). This variant has been reported in the compound heterozygous state in multiple individuals with nephronophthisis (See for example, Otto et al 2003. PubMed ID: 12872123; Chaki M et al 2011. PubMed ID: 21866095). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in INVS are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. | Chaki M | Kidney international | 2011 | PMID: 21866095 |
| Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. | Tory K | Kidney international | 2009 | PMID: 19177160 |
| 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 |
| Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. | Otto EA | Nature genetics | 2003 | PMID: 12872123 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=INVS | - | - | - | - |
Text-mined citations for rs753348470 ...
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 Jan 04, 2025
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.
ClinGen staff contributed the HGVS expression for this variant.