VCV000188952.8 - ClinVar

NM_014625.4(NPHS2):c.502C>T (p.Arg168Cys)

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/Likely 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_014625.4(NPHS2):c.502C>T (p.Arg168Cys)

Variation ID: 188952 Accession: VCV000188952.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q25.2 1: 179559711 (GRCh38) [ NCBI UCSC ] 1: 179528846 (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	Mar 29, 2015	Jun 23, 2024	Dec 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_014625.4:c.502C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055440.1:p.Arg168Cys	missense
NM_001297575.2:c.502C>T	NP_001284504.1:p.Arg168Cys	missense
NC_000001.11:g.179559711G>A
NC_000001.10:g.179528846G>A
NG_007535.1:g.21239C>T
LRG_887:g.21239C>T
	Q9NP85:p.Arg168Cys

... more HGVS ... less HGVS

Protein change

R168C

Other names

Canonical SPDI

NC_000001.11:179559710:G:A

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

ClinGen: CA199102 UniProtKB: Q9NP85#VAR_071221 dbSNP: rs786204583 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.
NPHS2		-	-	GRCh38 GRCh37	347	562

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.
Nephrotic syndrome, type 2	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 17, 2023	RCV000169326.7
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 4, 2023	RCV002515194.3

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.
Likely pathogenic (Sep 02, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Nephrotic syndrome, idiopathic, steroid-resistant (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220661.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 18596732‚ 14675423‚ 15253708‚ 24072147
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004049280.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023
Pathogenic (Dec 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003523922.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 15253708‚ 30721404‚ 32604935‚ 14675423‚ 15042551‚ 15059485‚ 26467726‚ 28385484 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the NPHS2 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the NPHS2 protein (p.Arg168Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nephrotic syndrome (PMID: 15253708, 30721404, 32604935). ClinVar contains an entry for this variant (Variation ID: 188952). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423). This variant disrupts the p.Arg168 amino acid residue in NPHS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14675423, 15042551, 15059485, 26467726, 28385484). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004191525.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Nephrotic syndrome, type 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Dr.Nikuei Genetic Center Accession: SCV005061414.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the NPHS2 protein (p.Arg168Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nephrotic syndrome (PMID: 15253708, 30721404, 32604935). ClinVar contains an entry for this variant (Variation ID: 188952). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423). This variant disrupts the p.Arg168 amino acid residue in NPHS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14675423, 15042551, 15059485, 26467726, 28385484). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, 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
Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis.	Park E	Journal of clinical medicine	2020	PMID: 32604935
Genetics of congenital and infantile nephrotic syndrome.	Sharief SN	World journal of pediatrics : WJP	2019	PMID: 30721404
Genetic mutation in Egyptian children with steroid-resistant nephrotic syndrome.	Thomas MM	Journal of the Formosan Medical Association = Taiwan yi zhi	2018	PMID: 28385484
Analysis of the genes responsible for steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis in Japanese patients by whole-exome sequencing analysis.	Ogino D	Journal of human genetics	2016	PMID: 26467726
NPHS2 gene in steroid-resistant nephrotic syndrome: prevalence, clinical course, and mutational spectrum in South-West Iranian children.	Basiratnia M	Iranian journal of kidney diseases	2013	PMID: 24072147
Steroid-resistant nephrotic syndrome.	Kitamura A	Kidney international	2008	PMID: 18596732
NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.	Weber S	Kidney international	2004	PMID: 15253708
[A novel mutation of NPHS2 identified in a Chinese family with steroid-resistant nephrotic syndrome].	Yu ZH	Zhonghua er ke za zhi = Chinese journal of pediatrics	2004	PMID: 15059485
Infantile steroid-resistant nephrotic syndrome associated with double homozygous mutations of podocin.	Caridi G	American journal of kidney diseases : the official journal of the National Kidney Foundation	2004	PMID: 15042551
Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations.	Roselli S	Traffic (Copenhagen, Denmark)	2004	PMID: 14675423

Text-mined citations for rs786204583 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_014625.4(NPHS2):c.502C>T (p.Arg168Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786204583 ...