Submissions for variant NM_004646.4(NPHS1):c.1930+10C>T

gnomAD frequency: 0.01025  dbSNP: rs76131336

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253090	SCV000310562	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000302690	SCV000411565	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.
Athena Diagnostics	RCV000712422	SCV000842915	benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000253090	SCV000919899	benign	not specified	2018-10-01	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.1930+10C>T 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. 5/5 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 0.0093 in 276940 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 2.78 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 benign. To our knowledge, no occurrence of c.1930+10C>T in individuals affected with Nephrotic Syndrome, Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000712422	SCV001113810	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000712422	SCV001872717	likely benign	not provided	2021-03-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294140	SCV002587576	benign	Atypical hemolytic-uremic syndrome	2022-10-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275393	SCV001460535	benign	Finnish congenital nephrotic syndrome	2020-09-16	no assertion criteria provided	clinical testing