Submissions for variant NM_004646.4(NPHS1):c.1758-8T>G

gnomAD frequency: 0.00387  dbSNP: rs187501631

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000889131	SCV001032793	benign	not provided	2025-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001127720	SCV001287063	uncertain significance	Congenital nephrotic syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000889131	SCV001804205	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271594	SCV002555929	benign	not specified	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.1758-8T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 269642 control chromosomes in the gnomAD database, including 3 homozygotes; occuring predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1758-8T>G in individuals affected with Nephrotic Syndrome, Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, one as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294400	SCV002587374	likely benign	Focal segmental glomerulosclerosis	2020-11-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001277288	SCV001464210	benign	Finnish congenital nephrotic syndrome	2019-11-11	no assertion criteria provided	clinical testing