VCV000237627.7 - ClinVar

NM_000272.5(NPHP1):c.(?_-45)_(*443_?)del

Germline

Classification

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000272.5(NPHP1):c.(?_-45)_(*443_?)del

Variation ID: 237627 Accession: VCV000237627.7

Type and length

Deletion, 81,727 bp

Location

Cytogenetic: 2q13 2: 110123336-110205062 (GRCh38) [ NCBI UCSC ] 2: 110880913-110962639 (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	Apr 16, 2017	Apr 15, 2024	Oct 10, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NC_000002.12:g.(?_110123336)_(110205062_?)del
NC_000002.11:g.(?_110880913)_(110962639_?)del

Protein change

Other names

NPHP1, DEL
DEL

Canonical SPDI

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

OMIM: 607100.0005 VarSome

Comment on variant

The deletion has been described at the genomic level, resulting in the loss of the transcript.

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
Gene	OMIM	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.
LOC126806306	-	-	-	GRCh38	-	88
NPHP1		-	-	GRCh38 GRCh37	899	1088

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.
Nephronophthisis	Pathogenic (1)	criteria provided, single submitter	Jan 18, 2017	RCV000227323.3
Nephronophthisis 1	Pathogenic (2)	criteria provided, single submitter	Oct 10, 2018	RCV001251510.5
Senior-Loken syndrome 1	Pathogenic (1)	no assertion criteria provided	Jul 1, 2004	RCV002518310.2
Joubert syndrome with renal defect	Pathogenic (1)	no assertion criteria provided	Jul 1, 2004	RCV002519780.2

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 18, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Nephronophthisis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284555.3 First in ClinVar: Jul 01, 2016 Last updated: Apr 16, 2017	Comment: A gross deletion of the genomic region encompassing the full coding sequence of the NPHP1 gene has been identified. The boundaries of this event are … (more) A gross deletion of the genomic region encompassing the full coding sequence of the NPHP1 gene has been identified. The boundaries of this event are unknown as the deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. Loss of NPHP1 is known to be pathogenic. Full gene deletions of NPHP1 have been reported in individuals with juvenile nephronophthisis, Bardet-Biedl syndrome, Joubert syndrome, and congenital ocular motor apraxia type Cogan (PMID: 8852662, 10620543, 24746959, 15138899, 10839884). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 10, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephronophthisis 1 Affected status: yes Allele origin: unknown	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV001427156.2 First in ClinVar: Aug 13, 2020 Last updated: Sep 18, 2020	Comment: A homozygous deletion encompassing the entire NPHP1 gene has been identified; NM_000272.3(NPHP1):c.(?_-94)_(462_?)del. The deletion includes at least the entire NPHP1 gene (NP_000263.2), and potentially extends … (more) A homozygous deletion encompassing the entire NPHP1 gene has been identified; NM_000272.3(NPHP1):c.(?_-94)_(462_?)del. The deletion includes at least the entire NPHP1 gene (NP_000263.2), and potentially extends into the adjacent gene, MALL (NP_005425.1). The variant is present in the general population at a frequency of 0.24% (Javorszky, E., et al. (2017)). The variant has been previously described as pathogenic in multiple patients with nephronophthisis. This deletion is the most frequent known cause of nephronophthisis (Chaki, M., et al. (2011), Lindstrand, A., et al. (2014), Hildebrandt, F., et al. (1997), Saunier, S., et al. (2000)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less) Clinical Features: renal transplant (present) Secondary finding: no
Pathogenic (Jul 01, 2004)	no assertion criteria provided Method: literature only	SENIOR-LOKEN SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023850.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 15, 2024	Publications: PubMed (6) PubMed: 8852662‚ 9326933‚ 10712196‚ 9856524‚ 15138899‚ 16155189 Comment on evidence: Nephronophthisis 1 Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et … (more) Nephronophthisis 1 Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et al., 1996; Hildebrandt et al., 1997; Saunier et al., 2000). Senior-Loken Syndrome 1 Caridi et al. (1998) described Senior-Loken syndrome (SLSN1; 266900), the association of nephronophthisis with autosomal recessive retinitis pigmentosa, in patients with homozygous deletion of the NPHP1 gene. Joubert Syndrome 4 In 2 sibs with a mild form of Joubert syndrome (JBTS4; 609583), Parisi et al. (2004) demonstrated homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with nephronophthisis alone. A hallmark of that disorder is cerebellar vermis hypoplasia with prominent superior cerebellar peduncles, creating the 'molar tooth sign' (MTS) on axial MRI. Parisi et al. (2004) suggested that the MTS may be relatively common in patients with juvenile nephronophthisis without classic symptoms of JS. In 4 patients with Joubert syndrome from 3 nonconsanguineous families, Parisi et al. (2006) identified homozygosity for deletion of the NPHP1 gene. The molar tooth sign in these patients had a distinctive appearance, with elongated but not thickened superior cerebellar peduncles. (less)
Pathogenic (Jul 01, 2004)	no assertion criteria provided Method: literature only	NEPHRONOPHTHISIS 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023849.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 15, 2024	Publications: PubMed (6) PubMed: 8852662‚ 9326933‚ 10712196‚ 9856524‚ 15138899‚ 16155189 Comment on evidence: Nephronophthisis 1 Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et … (more) Nephronophthisis 1 Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et al., 1996; Hildebrandt et al., 1997; Saunier et al., 2000). Senior-Loken Syndrome 1 Caridi et al. (1998) described Senior-Loken syndrome (SLSN1; 266900), the association of nephronophthisis with autosomal recessive retinitis pigmentosa, in patients with homozygous deletion of the NPHP1 gene. Joubert Syndrome 4 In 2 sibs with a mild form of Joubert syndrome (JBTS4; 609583), Parisi et al. (2004) demonstrated homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with nephronophthisis alone. A hallmark of that disorder is cerebellar vermis hypoplasia with prominent superior cerebellar peduncles, creating the 'molar tooth sign' (MTS) on axial MRI. Parisi et al. (2004) suggested that the MTS may be relatively common in patients with juvenile nephronophthisis without classic symptoms of JS. In 4 patients with Joubert syndrome from 3 nonconsanguineous families, Parisi et al. (2006) identified homozygosity for deletion of the NPHP1 gene. The molar tooth sign in these patients had a distinctive appearance, with elongated but not thickened superior cerebellar peduncles. (less)
Pathogenic (Jul 01, 2004)	no assertion criteria provided Method: literature only	JOUBERT SYNDROME 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023851.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 15, 2024	Publications: PubMed (6) PubMed: 8852662‚ 9326933‚ 10712196‚ 9856524‚ 15138899‚ 16155189 Comment on evidence: Nephronophthisis 1 Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et … (more) Nephronophthisis 1 Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et al., 1996; Hildebrandt et al., 1997; Saunier et al., 2000). Senior-Loken Syndrome 1 Caridi et al. (1998) described Senior-Loken syndrome (SLSN1; 266900), the association of nephronophthisis with autosomal recessive retinitis pigmentosa, in patients with homozygous deletion of the NPHP1 gene. Joubert Syndrome 4 In 2 sibs with a mild form of Joubert syndrome (JBTS4; 609583), Parisi et al. (2004) demonstrated homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with nephronophthisis alone. A hallmark of that disorder is cerebellar vermis hypoplasia with prominent superior cerebellar peduncles, creating the 'molar tooth sign' (MTS) on axial MRI. Parisi et al. (2004) suggested that the MTS may be relatively common in patients with juvenile nephronophthisis without classic symptoms of JS. In 4 patients with Joubert syndrome from 3 nonconsanguineous families, Parisi et al. (2006) identified homozygosity for deletion of the NPHP1 gene. The molar tooth sign in these patients had a distinctive appearance, with elongated but not thickened superior cerebellar peduncles. (less)

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the NPHP1 gene has been identified. The boundaries of this event are unknown as the deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. Loss of NPHP1 is known to be pathogenic. Full gene deletions of NPHP1 have been reported in individuals with juvenile nephronophthisis, Bardet-Biedl syndrome, Joubert syndrome, and congenital ocular motor apraxia type Cogan (PMID: 8852662, 10620543, 24746959, 15138899, 10839884). For these reasons, this variant has been classified as Pathogenic.

Comment:

A homozygous deletion encompassing the entire NPHP1 gene has been identified; NM_000272.3(NPHP1):c.(?_-94)_(*462_?)del. The deletion includes at least the entire NPHP1 gene (NP_000263.2), and potentially extends into the adjacent gene, MALL (NP_005425.1). The variant is present in the general population at a frequency of 0.24% (Javorszky, E., et al. (2017)). The variant has been previously described as pathogenic in multiple patients with nephronophthisis. This deletion is the most frequent known cause of nephronophthisis (Chaki, M., et al. (2011), Lindstrand, A., et al. (2014), Hildebrandt, F., et al. (1997), Saunier, S., et al. (2000)). Based on the information available at the time of curation, 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome.	Parisi MA	Journal of medical genetics	2006	PMID: 16155189
The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.	Parisi MA	American journal of human genetics	2004	PMID: 15138899
Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis.	Saunier S	American journal of human genetics	2000	PMID: 10712196
Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus.	Caridi G	American journal of kidney diseases : the official journal of the National Kidney Foundation	1998	PMID: 9856524
A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1.	Hildebrandt F	Nature genetics	1997	PMID: 9326933
Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis.	Konrad M	Human molecular genetics	1996	PMID: 8852662

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000272.5(NPHP1):c.(?_-45)_(*443_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...