Submissions for variant NM_004646.4(NPHS1):c.59-5C>G

gnomAD frequency: 0.01945  dbSNP: rs114595892

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253934	SCV000310582	benign	not specified		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000962680	SCV001109776	benign	not provided	2025-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001124813	SCV001283807	benign	Congenital nephrotic syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000253934	SCV001360989	benign	not specified	2019-10-17	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.59-5C>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0046 in 239616 control chromosomes, predominantly at a frequency of 0.062 within the African or African-American subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 18.48 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262358	SCV001440190	uncertain significance	Finnish congenital nephrotic syndrome	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000962680	SCV001871273	benign	not provided	2020-01-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19406966, 25525159)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294148	SCV002587232	benign	Focal segmental glomerulosclerosis	2022-03-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001262358	SCV001461581	benign	Finnish congenital nephrotic syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000253934	SCV001932435	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000253934	SCV001958804	benign	not specified		no assertion criteria provided	clinical testing