rs530318579

Positions:

• chr1-179559710-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014625.4(NPHS2):​c.503G>A​(p.Arg168His) variant causes a missense change. The variant allele was found at a frequency of 0.0000145 in 1,591,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.91

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 130 pathogenic changes around while only 3 benign (98%) in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179559711-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-179559710-C-T is Pathogenic according to our data. Variant chr1-179559710-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179559710-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.503G>A	p.Arg168His	missense_variant	4/8	ENST00000367615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.503G>A	p.Arg168His	missense_variant	4/8	1	NM_014625.4	P1
NPHS2	ENST00000367616.4	c.503G>A	p.Arg168His	missense_variant	4/7	1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151716 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000136 AC: 3 AN: 221108 Hom.: 0 AF XY: 0.00000844 AC XY: 1 AN XY: 118432

Gnomad AFR exome AF: 0.0000739

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000153 AC: 22 AN: 1439656 Hom.: 0 Cov.: 30 AF XY: 0.00000980 AC XY: 7 AN XY: 714014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74160

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:8

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 30, 2021	NPHS2 c.503G>A has been identified in the compound heterozygote or homozygous state in multiple individuals with steroid-resistant nephrotic syndrome. This NPHS2 variant (rs530318579) is rare (<0.1%) in a large population dataset (gnomAD: 3/221108 total alleles; 0.0014%; no homozygotes). There is an entry for this variant in ClinVar (Variation ID: 188730). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across most species assessed. There is functional evidence that this variant causes mislocalization of the NPHS2 protein. We consider NPHS2 c.503G>A to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2020	Variant summary: NPHS2 c.503G>A (p.Arg168His) results in a non-conservative amino acid change in 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 1.4e-05 in 221108 control chromosomes. c.503G>A has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 (examples- Weber_2004, Ruf_2004, Mann_2019). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the variant results in mislocalization of the protein to the endoplasmic reticulum (examples- Roselli_2004, Fan_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 01, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 30, 2023	This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 15042551, 15059485, 26467726, 28385484). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423). 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. ClinVar contains an entry for this variant (Variation ID: 188730). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the NPHS2 protein (p.Arg168His). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2017	- -

Steroid-resistant nephrotic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Finnish congenital nephrotic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Vasylyeva lab, Texas Tech University Health Sciences Center

-

- -

Nephrotic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Sep 06, 2018

This patient is an apparent homozygote for a known pathogenic variant, c.503G>A (p.Arg168His), in exon 4 of the NPHS2 gene. This variant has been previously reported in the homozygote state, and also in compound heterozygote with another pathogenic NPHS2 variant, in patients with steroid resistant nephrotic syndrome (SRNS) (Weber et al 2004 Kid Int 66:571-79). In vitro study of the NPHS2 p.Arg168His mutant in cultured podocytes showed the mutant proteins were retained in the endoplasmic reticulum (ER). This caused the mislocalisation of other critical slit diaphragm molecules, and significantly upregulated the ER stress markers, resulting in podocyte apoptosis and the cause of SRNS (Fan et al 2009 Genes Cells 14:1079-90). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.93		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.93
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs530318579; hg19: chr1-179528845; COSMIC: COSV62635119; COSMIC: COSV62635119;