NM_004646.4(NPHS1):c.1219C>T (p.Arg407Trp) AND Finnish congenital nephrotic syndrome

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Feb 25, 2024
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:: RCV000049843.9

Allele description [Variation Report for NM_004646.4(NPHS1):c.1219C>T (p.Arg407Trp)]

NM_004646.4(NPHS1):c.1219C>T (p.Arg407Trp)

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.1219C>T (p.Arg407Trp)

HGVS:

NC_000019.10:g.35848349G>A
NG_013356.2:g.25939C>T
NG_051206.1:g.1715G>A
NM_004646.4:c.1219C>TMANE SELECT
NP_004637.1:p.Arg407Trp
NP_004637.1:p.Arg407Trp
LRG_693t1:c.1219C>T
LRG_693:g.25939C>T
LRG_693p1:p.Arg407Trp
NC_000019.9:g.36339251G>A
NM_004646.3:c.1219C>T
O60500:p.Arg407Trp

Protein change:

R407W

Links:

UniProtKB: O60500#VAR_064206; dbSNP: rs386833874

NCBI 1000 Genomes Browser:

rs386833874

Molecular consequence:

NM_004646.4:c.1219C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Finnish congenital nephrotic syndrome (NPHS1)
Synonyms:: NEPHROTIC SYNDROME, TYPE 1; Nephrosis 1, congenital, Finnish type; Congenital nephrotic syndrome 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
SCV000082252	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV000795959	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Nov 30, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25349199, 20172850 Citation Link,
SCV002015021	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 22, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25349199, 20172850, 30215773, 31655822 Citation Link,
SCV002087089	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 10, 2020)	germline	clinical testing
SCV002570249	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 29, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20172850, 25349199, 30215773, 31655822, 33980730, 34859019, 25741868
SCV002816150	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 31, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004123150	Vasylyeva lab, Texas Tech University Health Sciences Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 22, 2021)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 34859019, 33980730, 31655822, 25349199, 25741868
SCV004191385	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082252

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

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

Management of children with congenital nephrotic syndrome: challenging treatment paradigms.

Dufek S, Holtta T, Trautmann A, Ylinen E, Alpay H, Ariceta G, Aufricht C, Bacchetta J, Bakkaloglu SA, Bayazit A, Cicek RY, Dursun I, Duzova A, Ekim M, Iancu D, Jankauskiene A, Klaus G, Paglialonga F, Pasini A, Printza N, Said Conti V, do Sameiro Faria M, et al.

Nephrol Dial Transplant. 2019 Aug 1;34(8):1369-1377. doi: 10.1093/ndt/gfy165.

PubMed [citation]

PMID:: 30215773

See all PubMed Citations (7)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082252.1

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

Description

Converted during submission to Likely pathogenic.

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

From Counsyl, SCV000795959.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002015021.1

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

Description

Variant summary: NPHS1 c.1219C>T (p.Arg407Trp) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251390 control chromosomes. c.1219C>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 in homozygous or compound heterozygous states (e.g. Schoeb_2010, Sadowski_2015, Dufek_2019, Sinha_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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., SCV002087089.1

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV002570249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

NPHS1 c.1219C>T has been identified in the homozygous and compound heterozygous state in multiple individuals with nephrotic syndrome, type 1. This variant (rs386833874) is rare (<0.1%) in a large population dataset (gnomAD:6/282766 total alleles; 0.002122%; no homozygotes) and has been reported in ClinVar (Variation ID: 56430). Three bioinformatic tools queried predict that this substitution would be damaging and the arginine residue at this position is evolutionarily conserved across most mammalian species assessed. We consider NPHS1 c.1219C>T to be likely 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 Fulgent Genetics, Fulgent Genetics, SCV002816150.1

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

From Vasylyeva lab, Texas Tech University Health Sciences Center, SCV004123150.1

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

#	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, SCV004191385.2

#	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

Last Updated: Jun 17, 2024

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