VCV000056466.9 - ClinVar

NM_004646.4(NPHS1):c.2172_2173del (p.Glu725fs)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (2)

2 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004646.4(NPHS1):c.2172_2173del (p.Glu725fs)

Variation ID: 56466 Accession: VCV000056466.9

Type and length

Deletion, 2 bp

Location

Cytogenetic: 19q13.12 19: 35844142-35844143 (GRCh38) [ NCBI UCSC ] 19: 36335044-36335045 (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	Jul 24, 2013	Feb 15, 2026	Nov 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_004646.4:c.2172_2173del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004637.1:p.Glu725fs	frameshift
NM_004646.3:c.2172_2173delTG
NC_000019.10:g.35844142_35844143del
NC_000019.9:g.36335044_36335045del
NG_013356.2:g.30145_30146del
LRG_693:g.30145_30146del
LRG_693t1:c.2172_2173del

... more HGVS ... less HGVS

Protein change

E725fs

Other names

Canonical SPDI

NC_000019.10:35844141:CA:

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA250173 dbSNP: rs386833906 VarSome

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.
NPHS1		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1968	2177

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.
Finnish congenital nephrotic syndrome	Pathogenic (3)	criteria provided, single submitter	Nov 8, 2022	RCV000049879.4
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 25, 2021	RCV001853053.6

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.	Expand all rows Collapse all rows 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 (Nov 08, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Finnish congenital nephrotic syndrome	Baylor Genetics Accession: SCV004191494.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Feb 25, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002235638.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 11317351‚ 11854170‚ 12039988‚ 16703378 Comment: show This sequence change creates a premature translational stop signal (p.Glu725Glyfs*25) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with nephrotic syndrome (PMID: 16703378). ClinVar contains an entry for this variant (Variation ID: 56466). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Finnish congenital nephrotic syndrome (Autosomal recessive inheritance)	Department of Traditional Chinese Medicine, Fujian Provincial Hospital Accession: SCV002599093.1 First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022	Publications: PubMed (1) PubMed: 16703378 Observation: 1 Collection method: research Allele origin: de novo Affected status: no more Observation 1 Collection method: research Allele origin: de novo Affected status: no Age: 0-9 years

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Finnish congenital nephrotic syndrome	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082288.2 First in ClinVar: Jul 24, 2013 Last updated: Jun 08, 2025 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: show Converted during submission from probable-pathogenic to Likely pathogenic. (less) Observation: 1 Collection method: not provided Allele origin: unknown Affected status: not provided Observation 1 Collection method: not provided Allele origin: unknown Affected status: not provided

Comment:

This sequence change creates a premature translational stop signal (p.Glu725Glyfs*25) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with nephrotic syndrome (PMID: 16703378). ClinVar contains an entry for this variant (Variation ID: 56466). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Neonatal nephrotic presentation of a child with heterozygous NPHS1 mutation.	Lemley KV	Pediatric nephrology (Berlin, Germany)	2006	PMID: 16703378
Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions.	Rantanen M	Journal of the American Society of Nephrology : JASN	2002	PMID: 12039988
Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.	Koziell A	Human molecular genetics	2002	PMID: 11854170
Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome.	Beltcheva O	Human mutation	2001	PMID: 11317351

Text-mined citations for rs386833906 ...

These 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 Apr 13, 2026