NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp) AND Nephrotic syndrome, type 2

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Oct 10, 2023
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:: RCV000005700.16

Allele description [Variation Report for NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)]

NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)

Genes:

NPHS2:NPHS2 stomatin family member, podocin [Gene - OMIM - HGNC]
AXDND1:axonemal dynein light chain domain containing 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.2

Genomic location:

Preferred name:

NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)

HGVS:

NC_000001.11:g.179552605G>A
NG_007535.1:g.28345C>T
NG_033075.1:g.191886G>A
NM_001297575.2:c.667C>T
NM_014625.4:c.871C>TMANE SELECT
NM_144696.6:c.3032-1907G>AMANE SELECT
NP_001284504.1:p.Arg223Trp
NP_055440.1:p.Arg291Trp
NP_055440.1:p.Arg291Trp
LRG_887t1:c.871C>T
LRG_887:g.28345C>T
LRG_887p1:p.Arg291Trp
NC_000001.10:g.179521740G>A
NM_014625.2:c.871C>T
NM_014625.3:c.871C>T
Q9NP85:p.Arg291Trp

Protein change:

R223W; ARG291TRP

Links:

UniProtKB: Q9NP85#VAR_010236; OMIM: 604766.0010; dbSNP: rs74315348

NCBI 1000 Genomes Browser:

rs74315348

Molecular consequence:

NM_144696.6:c.3032-1907G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001297575.2:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014625.4:c.871C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Nephrotic syndrome, type 2 (NPHS2)
Synonyms:: Nephrotic syndrome, steroid-resistant, autosomal recessive; Hereditary nephrotic syndrome
Identifiers:: MONDO: MONDO:0010974; MedGen: C1868672; Orphanet: 656; OMIM: 600995

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025882	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2000)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8589695, 10742096
SCV000220295	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 5, 2014)	unknown	literature only	PubMed (10) [See all records that cite these PMIDs] 15327385, 24509478, 15769810, 14978175, 11805166, 15496146, 15817495, 12464671, 14675423, 10742096 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000863895	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	no assertion criteria provided	Pathogenic (Jun 4, 2018)	germline	clinical testing
SCV000893929	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001360832	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 22, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15327385, 25349199, 14675423, 30260545, 26668027, 24509478 Citation Link,
SCV004049255	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004191530	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2023)	unknown	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	no	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	germline	yes	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	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis.

Fuchshuber A, Jean G, Gribouval O, Gubler MC, Broyer M, Beckmann JS, Niaudet P, Antignac C.

Hum Mol Genet. 1995 Nov;4(11):2155-8.

PubMed [citation]

PMID:: 8589695

Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children.

Yu Z, Ding J, Huang J, Yao Y, Xiao H, Zhang J, Liu J, Yang J.

Nephrol Dial Transplant. 2005 May;20(5):902-8. Epub 2005 Mar 15.

PubMed [citation]

PMID:: 15769810

See all PubMed Citations (15)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000025882.2

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

Description

In a family with autosomal recessive steroid-resistant nephrotic syndrome (600995) previously reported by Fuchshuber et al. (1995), Boute et al. (2000) identified an 871C-T transition in exon 7 of the NPHS2 gene, which resulted in an arg291-to-trp (R291W) substitution. This mutation was identified on the paternal allele; a mutation on the maternal allele was not identified.

#	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 Counsyl, SCV000220295.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (10)

#	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 Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, SCV000863895.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893929.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: NPHS2 c.871C>T (p.Arg291Trp) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five 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 249882 control chromosomes. c.871C>T has been reported in the literature in compound heterozygous and homozygous genotypes with another variant p.R229Q among multiple individuals affected with Steroid Resistant Nephrotic syndrome (SRNS) (Zhang_2004, Tory_2014, Buscher_2016, Sadowski_2015, Miko_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that demonstrates that p.Arg291Trp podocin mutant localizes to the late endosomes (Roselli_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as 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 Genome-Nilou Lab, SCV004049255.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004191530.1

#	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

Last Updated: Apr 20, 2024

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