NM_004646.4(NPHS1):c.1379G>A (p.Arg460Gln) AND Finnish congenital nephrotic syndrome

Germline classification:: Pathogenic/Likely pathogenic (12 submissions)
Last evaluated:: Nov 26, 2025
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:: RCV000049851.25

Allele description [Variation Report for NM_004646.4(NPHS1):c.1379G>A (p.Arg460Gln)]

NM_004646.4(NPHS1):c.1379G>A (p.Arg460Gln)

Gene:

NPHS1:NPHS1 adhesion molecule, nephrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.12

Genomic location:

Preferred name:

NM_004646.4(NPHS1):c.1379G>A (p.Arg460Gln)

HGVS:

NC_000019.10:g.35848102C>T
NG_013356.2:g.26186G>A
NG_051206.1:g.1468C>T
NM_004646.4:c.1379G>AMANE SELECT
NP_004637.1:p.Arg460Gln
NP_004637.1:p.Arg460Gln
LRG_693t1:c.1379G>A
LRG_693:g.26186G>A
LRG_693p1:p.Arg460Gln
NC_000019.9:g.36339004C>T
NM_004646.3:c.1379G>A
O60500:p.Arg460Gln

Protein change:

R460Q

Links:

UniProtKB: O60500#VAR_064209; dbSNP: rs386833880

Molecular consequence:

NM_004646.4:c.1379G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Finnish congenital nephrotic syndrome (NPHS1)
Synonyms:: NEPHROTIC SYNDROME, TYPE 1
Identifiers:: MONDO: MONDO:0009732; MedGen: C0403399; Orphanet: 839; OMIM: 256300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082260	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	Likely pathogenic	unknown	not provided
SCV000220658	Counsyl	no assertion criteria provided	Likely pathogenic (Aug 29, 2014)	unknown	literature only	PubMed (9) [See all records that cite these PMIDs] 20507940, 18503012, 11854170, 15780077, 20172850, 19194555, 11317351, 18614772, 21415313
SCV000915829	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Jul 20, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15780077, 20172850, 20507940, 19194555, 18503012 Citation Link,
SCV000917904	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 14, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11854170, 18614772, 18503012 Citation Link,
SCV001460540	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Nov 26, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 37204080, 31937884 Citation Link,
SCV002059163	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 3, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21125408, 11317351, 30655312, 19194555, 25741868
SCV002781746	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004024494	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004123152	Vasylyeva lab, Texas Tech University Health Sciences Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19194555, 21125408, 21415313, 25741868
SCV004191378	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 7, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005873636	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	criteria provided, single submitter (Submitter's publication)	Likely pathogenic (Jan 19, 2021)	unknown	clinical testing
SCV006552642	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 10, 2025)	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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
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	research, clinical testing
South East Asian	unknown	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome.

Sako M, Nakanishi K, Obana M, Yata N, Hoshii S, Takahashi S, Wada N, Takahashi Y, Kaku Y, Satomura K, Ikeda M, Honda M, Iijima K, Yoshikawa N.

Kidney Int. 2005 Apr;67(4):1248-55.

PubMed [citation]

PMID:: 15780077

Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS).

Schoeb DS, Chernin G, Heeringa SF, Matejas V, Held S, Vega-Warner V, Bockenhauer D, Vlangos CN, Moorani KN, Neuhaus TJ, Kari JA, MacDonald J, Saisawat P, Ashraf S, Ovunc B, Zenker M, Hildebrandt F; Gesselschaft für Paediatrische Nephrologie (GPN) Study Group.

Nephrol Dial Transplant. 2010 Sep;25(9):2970-6. doi: 10.1093/ndt/gfq088. Epub 2010 Feb 18.

PubMed [citation]

PMID:: 20172850
PMCID:: PMC2948833

See all PubMed Citations (14)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082260.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

Description

Converted during submission from probable-pathogenic to Likely pathogenic.

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

From Counsyl, SCV000220658.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (9)

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	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 Illumina Laboratory Services, Illumina, SCV000915829.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Across a selection of the available literature, the NPHS1 c.1379G>A (p.Arg460Gln) variant has been identified in at least 11 individuals with congenital Finnish nephrosis. Specifically, the p.Arg460Gln variant was reported in a homozygous state in six individuals, in a compound heterozygous state in three individuals, and in a heterozygous state in two individuals (Sako et al. 2005; Heeringa et al. 2008; Lee et al. 2009; Machuca et al. 2010; Schoeb et al. 2010). The p.Arg460Gln variant was also found in a heterozygous state in the unaffected mother of an affected heterozygote (Sako et al. 2005). Two of the compound heterozygotes have null variants on the second allele (Heeringa et al. 2008; Machuca et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000183 in the Other population of the Genome Aggregation Database but this is based on one allele so the variant is presumed to be rare. Based on the evidence, the p.Arg460Gln variant is classified as pathogenic for congenital nephrotic syndrome. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917904.1

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

Description

Variant summary: The NPHS1 c.1379G>A (p.Arg460Gln) variant located in the Immunoglobulin-like fold domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/215308 control chromosomes at a frequency of 0.0000093, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Multiple publications have cited the variant in homozygous and compound heterozygous affected pts. A functional study, Philippe_2008 indicates that the variant was shown to traffic normally in the cell and to homodimerize and to heterodimerize with NEPH1, but they suggest that additional studies are needed to evaluate whether missense variants that traffic to the membrane affect nephrin phosphorylation, actin reorganization in the cytoskeleton of podocytes, or downstream signaling events involved in transcriptional regulation and apoptosis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.

#	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 Natera, Inc., SCV001460540.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.1379G>A variant in NPHS1 is a missense variant predicted to cause substitution of arginine to glutamine at amino acid 460. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 37204080, 31937884). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic.

#	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 3billion, SCV002059163.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.46 (>=0.2, moderate evidence for spliceogenicity)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000056438 /PMID: 11317351 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 19194555, 21125408, 30655312). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002781746.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV004024494.2

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

#	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

From Vasylyeva lab, Texas Tech University Health Sciences Center, SCV004123152.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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

From Baylor Genetics, SCV004191378.2

#	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 Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare, SCV005873636.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South East Asian	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV006552642.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 20, 2026

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