rs530318579
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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
Consequence
NM_014625.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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: 1AN: 151716Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000136 AC: 3AN: 221108Hom.: 0 AF XY: 0.00000844 AC XY: 1AN XY: 118432
GnomAD4 exome AF: 0.0000153 AC: 22AN: 1439656Hom.: 0 Cov.: 30 AF XY: 0.00000980 AC XY: 7AN XY: 714014
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151834Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74160
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at