Submissions for variant NM_004646.4(NPHS1):c.2606_2607dup (p.Asn870fs)

dbSNP: rs386833921

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000049895	SCV001163803	pathogenic	Finnish congenital nephrotic syndrome	2024-03-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383055	SCV001582074	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn870Profs*36) 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). This variant is present in population databases (rs386833921, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 9915943, 19406966, 23949594). ClinVar contains an entry for this variant (Variation ID: 56482). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049895	SCV001748783	pathogenic	Finnish congenital nephrotic syndrome	2021-07-01	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.2606_2607dupCC (p.Asn870ProfsX36) 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 1.6e-05 in 243772 control chromosomes (gnomAD). The variant, c.2606_2607dupCC, has been reported in the literature in several compound heterozygous individuals affected with Nephrotic Syndrome, Type 1 (Lenkkeri_1999, Hinkes_2007, Machuca_2010, Wong_2013, Sadowski_2014). These data indicate that the variant is likely to be associated with disease. 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV001383055	SCV001879944	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. 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.
Fulgent Genetics, Fulgent Genetics	RCV000049895	SCV002804567	pathogenic	Finnish congenital nephrotic syndrome	2022-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001383055	SCV004027929	pathogenic	not provided	2023-02-15	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9915943, 23949594)
Illumina Laboratory Services, Illumina	RCV000049895	SCV004101303	pathogenic	Finnish congenital nephrotic syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The NPHS1 c.2606_2607dup (p.Asn870ProfsTer36) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in four individuals with congenital nephrotic syndrome (CNS). In two individuals, the p.Asn870ProfsTer36 variant was identified in trans with a frameshift variant and a pathogenic missense (PMID: 17371932; 25349199). A second variant was not reported for the two other individuals. (PMID: 9915943; 20507940). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.2606_2607dup (p.Asn870ProfsTer36) variant is classified as pathogenic for congenital nephrotic syndrome.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049895	SCV000082304	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000049895	SCV002087078	pathogenic	Finnish congenital nephrotic syndrome	2020-08-19	no assertion criteria provided	clinical testing