Submissions for variant NM_004646.4(NPHS1):c.574C>T (p.Gln192Ter)

gnomAD frequency: 0.00002  dbSNP: rs386833953

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812623	SCV000952942	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs386833953, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with nephrotic syndrome (PMID: 20172850). ClinVar contains an entry for this variant (Variation ID: 56515). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln192*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049928	SCV001623299	pathogenic	Finnish congenital nephrotic syndrome	2021-04-18	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.574C>T (p.Gln192X) 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 4e-06 in 251482 control chromosomes. c.574C>T has been reported in the literature in at-least one individual affected with Nephrotic Syndrome, Type 1 (Steroid resistant) and has also been subsequently cited by others (example, Schoeb_2010, Lovric_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping an evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000049928	SCV002781389	pathogenic	Finnish congenital nephrotic syndrome	2022-04-17	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049928	SCV000082337	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.