Disease | Nephrotic syndrome |
|---|
Inheritance | Autosomal recessive |
Prevalence | 1/8,200 in Finland, unknown worldwide Source: ORPHA:839 |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen - dosage only, curated as HI 30 (AR phenotype). GenCC - definitive/Strong for AR congenital nephrotic syndrome by myriad and Invitae. BabySeq - Definitive for congenital nephrotic syndrome (PMID: 12495287, 11317351, 9660941, 9915943, 10577936, 12495287). |
Clinical Validity Scoring Notes and points | From BabySeq: 12495287 11317351 - mutation update, summarizes prior studies. 9660941 1998 - Previous studies loalized the NPHS1 gene, and in this study they report on the gene and variant s in the gene in individuals with congenital nephrotic syndrome. Table 1 reports individuals: Fin-major [NM_004646.4: c.121_122delCT; p.(Leu41Aspfs*50)] - present in 1% of Finnish chr in gnomAD (c/w AR pheno), NMD+ (2 POINTS). It was found in 57 chromosomes. Fin-minor c.3325C>T p.R1109* - 0.06% in gnomAD in Finnish population (c/w AR pheno), NMD+, found in 10 chromosomes, 2 POINTS nt1306(ins2), aka c.1307_1308dupAC p.(Val437Thrfs*2) - 1 allele gnomAD, NMD+, in patient NA-1 - Homozygous (2 POINTS) nt3250(insG), aka c.3250dupG p.(Val1084Glyfs*12) - 0.01% in African chr in gnomAD, NMD+ (2 POINTS) in patient NA-2 - cmp het with this variant and Fin-Major (2 POINTS)
9915943 (1999) - author overlap with 9660941, but show more patients in table 1 with truncations Fin Major reported hom in patients 6, 16, 19, 20. Counting 3 patients, 3x2 = 6 points Many additional truncations, but reached max genetic evidence 12 points.
PMID: 12495287 (2002) - Didn’t review fully for points, but will use for replication over time. Tested NPHS1 in Italian patients, found 13 mutations including deletions, insertions, nonsense and missense mutations.
17371932 |
Clinical Validity Points Total | 12 Source: |
Clinical Validity Classification | Expand |
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| title | Classifications (pts) |
|---|
| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Definitive Source: 9660941, 9915943, 12495287 |
Molecular Mechanism | Expand |
|---|
| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function See Clinical Validity Scoring Notes and points - Many truncating/LOF NMD+ variants reported. Source: 9660941, 9915943, 12495287 |
Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | Congenital to pediatric PMID: 34436835 |
Severity | Expand |
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| Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. |
| Moderate |
Clinical Features | Severe proteinuria presenting with increased urine protein/creatinine ratio, hypoalbuminemia, and edema. Typically it is resistant to steroid treatment and can progress to end-stage renal failure Sources: PMID: 34436835 |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | Expand |
|---|
| - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited |
| The NPHS1 gene is associated with autosomal recessive nephrotic syndrome, which is characterized by severe proteinuria presenting with increased urine protein/creatinine ratio, hypoalbuminemia, and edema (PMID: 9660941, 9915943, 12495287). It is often steroid-resistant and can present congenitally or in early childhood (PMID: 34436835). |
Case ID, Curator name, Date, Jira ticket link | D-110607902-BH-4018-P-A, Andrea Oza 12/14/2023 |