Submissions for variant NM_004646.4(NPHS1):c.866G>A (p.Trp289Ter)

dbSNP: rs781584590

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411580	SCV000486357	likely pathogenic	Finnish congenital nephrotic syndrome	2016-05-19	criteria provided, single submitter	clinical testing
Invitae	RCV001850950	SCV002169160	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 370925). This premature translational stop signal has been observed in individual(s) with congenital nephrotic syndrome (PMID: 20172850). 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 creates a premature translational stop signal (p.Trp289*) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411580	SCV002500093	pathogenic	Finnish congenital nephrotic syndrome	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.866G>A (p.Trp289X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 245292 control chromosomes (gnomAD). c.866G>A has been reported in the literature in multiple homozygous individuals affected with Nephrotic Syndrome (examples: Cil_2015 and Bucher_2016). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Vasylyeva lab, Texas Tech University Health Sciences Center	RCV000411580	SCV004123149	pathogenic	Finnish congenital nephrotic syndrome	2022-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411580	SCV005053653	pathogenic	Finnish congenital nephrotic syndrome	2024-02-14	criteria provided, single submitter	clinical testing