NM_014425.5(INVS):c.1453del (p.Gln485fs) AND Infantile nephronophthisis

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 2, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012741.37

Allele description [Variation Report for NM_014425.5(INVS):c.1453del (p.Gln485fs)]

NM_014425.5(INVS):c.1453del (p.Gln485fs)

Gene:

INVS:inversin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

9q31.1

Genomic location:

Preferred name:

NM_014425.5(INVS):c.1453del (p.Gln485fs)

Other names:

p.Gln485Lysfs*25

HGVS:

NC_000009.12:g.100253125del
NG_008316.1:g.158897del
NM_001318381.2:c.1165del
NM_001318382.2:c.475del
NM_014425.5:c.1453delMANE SELECT
NP_001305310.1:p.Gln389fs
NP_001305311.1:p.Gln159fs
NP_055240.2:p.Gln485fs
NC_000009.11:g.103015407del
NM_014425.3:c.1453del
NM_014425.3:c.1453delC
NM_014425.4:c.1453del
NM_014425.4:c.1453delC
NR_134606.2:n.1651del

Note:

ClinGen staff contributed the HGVS expression for this variant.

Protein change:

Q159fs

Links:

OMIM: 243305.0005; dbSNP: rs753348470

NCBI 1000 Genomes Browser:

rs753348470

Molecular consequence:

NM_001318381.2:c.1165del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318382.2:c.475del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014425.5:c.1453del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_134606.2:n.1651del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Infantile nephronophthisis (NPHP2)
Synonyms:: Nephronophthisis 2; Nephronophthisis 2, infantile
Identifiers:: MONDO: MONDO:0011190; MedGen: C1865872; Orphanet: 655; OMIM: 602088

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000032976	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000916243	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 4, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12872123, 19177160, 21866095 Citation Link,
SCV001752607	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061581	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Schermer B, Obara T, O'Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J, Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T, Kispert A, Wolf MT, Gagnadoux MF, Nivet H, Antignac C, Walz G, Drummond IA, Benzing T, Hildebrandt F.

Nat Genet. 2003 Aug;34(4):413-20.

PubMed [citation]

PMID:: 12872123
PMCID:: PMC3732175

Mutations of NPHP2 and NPHP3 in infantile nephronophthisis.

Tory K, Rousset-Rouvière C, Gubler MC, Morinière V, Pawtowski A, Becker C, Guyot C, Gié S, Frishberg Y, Nivet H, Deschênes G, Cochat P, Gagnadoux MF, Saunier S, Antignac C, Salomon R.

Kidney Int. 2009 Apr;75(8):839-47. doi: 10.1038/ki.2008.662. Epub 2009 Jan 28.

PubMed [citation]

PMID:: 19177160

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000032976.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000916243.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV001752607.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061581.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1, PM2, PM3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 4, 2025

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