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:

• 9660941, 9915943, 12495287

Clinical Validity Classification

Definitive

Source: 9660941, 9915943, 12495287

Molecular Mechanism

Loss of function

See Clinical Validity Scoring Notes and points - Many truncating/LOF NMD+ variants reported.

Source: 9660941, 9915943, 12495287

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Congenital to pediatric

PMID: 34436835

Severity

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

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