rs780761368
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_014625.4(NPHS2):c.851C>T(p.Ala284Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,620 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A284A) has been classified as Likely benign.
Frequency
Consequence
NM_014625.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS2 | NM_014625.4 | c.851C>T | p.Ala284Val | missense_variant | 7/8 | ENST00000367615.9 | |
AXDND1 | NM_144696.6 | c.3032-1887G>A | intron_variant | ENST00000367618.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS2 | ENST00000367615.9 | c.851C>T | p.Ala284Val | missense_variant | 7/8 | 1 | NM_014625.4 | P1 | |
AXDND1 | ENST00000367618.8 | c.3032-1887G>A | intron_variant | 1 | NM_144696.6 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249998Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135218
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461466Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727032
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the NPHS2 protein (p.Ala284Val). This variant is present in population databases (rs780761368, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of steroid-resistant nephrotic syndrome (PMID: 11805166, 16354237, 18823551, 23349334, 23515051, 29982877). It has been reported in trans with the variant p.Arg229Gln in related affected individuals. This suggests that the combination of p.Arg229Gln and this variant may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 562398). 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%. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 24509478). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 11, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24509478, 21415313, 26211502, 16354237, 16898497, 26420286, 29982877, 32604935, 11805166, 23515051, 23349334, 19876656, 21355056, 19145239, 14978175, 12464671, 15253708, 18823551, 30586318, 35253369, 38765578, 37850020, 37547535) - |
Nephrotic syndrome, type 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 25, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Idiopathic nephrotic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 10, 2022 | Variant summary: NPHS2 c.851C>T (p.Ala284Val) 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 4e-05 in 150926 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.851C>T, has been reported in the literature in multiple homozygous individuals affected with Nephrotic Syndrome Type 2, which progressed to end-stage renal disease (e.g. Tsukaguchi_2002, Karle_2002, Kitzler_2018). This variant was also reported in compound heterozygous state in numerous patients with a well-reported, frequent, genotype-dependent risk variant p.R229Q (e.g. Tsukaguchi_2002, Machuca_2009, Santin_2011), and occasionally also with other (potentially) pathogenic variants in trans (e.g. Park_2020). These data indicate that the variant is very likely to be associated with disease. An extensive study performed by Tory_2014, demonstrated that the A284V podocin protein was mislocalized in the cytoplasmic compartment (either when coexpressed with the WT or with the R229Q podocin), in contrast, while WT podocin reached the plasma membrane, podocin R229Q was retained in the cytoplasm in cells coexpressing podocin A284V (on the other hand, both the WT podocin and podocin R229Q were localized to the plasma membrane when coexpressed together); authors concluded that these interactions mimicked a dominant-negative effect of A284V on the R229Q variant protein. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at