Submissions for variant NM_014625.4(NPHS2):c.59C>T (p.Pro20Leu)

gnomAD frequency: 0.00425  dbSNP: rs74315344

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588524	SCV000699383	likely benign	not provided	2016-03-04	criteria provided, single submitter	clinical testing	Variant summary: The c.59C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Leu. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO, MutationTaster not captured due to low reliability index). This variant is found in 92/7048 control chromosomes (1 homozygote) at a frequency of 0.0130533, which is about 7 times of maximal expected frequency of a pathogenic allele (0.0017678), suggesting this variant is benign. Although this variant was classified as pathogenic by OMIM via ClinVar, multiple recent literatures suggested this variant was a polymorphism based on the evidence of co-occurrences with a pathogenic variant and homozygous occurrences in controls. Taken together, this variant was classified as likely benign.
Athena Diagnostics	RCV000588524	SCV000842931	benign	not provided	2018-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000005696	SCV001254354	benign	Nephrotic syndrome, type 2	2017-04-27	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000005696	SCV001439909	uncertain significance	Nephrotic syndrome, type 2	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588524	SCV001729493	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005696	SCV001737178	benign	Nephrotic syndrome, type 2	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000588524	SCV001950621	benign	not provided	2020-07-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30450462, 23349334, 20947785, 22995991, 10742096, 27884173, 15042551, 26211502, 27885584, 30721404, 28712774)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000005696	SCV001984407	benign	Nephrotic syndrome, type 2	2020-03-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293977	SCV002587222	likely benign	Focal segmental glomerulosclerosis	2022-05-19	criteria provided, single submitter	clinical testing
Vasylyeva lab, Texas Tech University Health Sciences Center	RCV003407281	SCV004123143	uncertain significance	Finnish congenital nephrotic syndrome	2019-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588524	SCV004123861	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	NPHS2: BS2
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003150926	SCV004847490	likely benign	not specified	2024-04-15	criteria provided, single submitter	clinical testing	The p.Pro20Leu variant in NPHS2 is classified as likely benign because it has been identified in 1.0% (57/5542) of Middle Eastern and 0.98% (674/68276) of African/African American chromosomes, including 8 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), which is higher than the expected frequency of a pathogenic allele in NPHS2 causing disease. ACMG/AMP Criteria applied: BS1.
OMIM	RCV000005696	SCV000025878	pathogenic	Nephrotic syndrome, type 2	2003-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001276841	SCV001463424	likely benign	Steroid-resistant nephrotic syndrome	2020-06-11	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150926	SCV003839789	likely benign	not specified	2022-05-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914811	SCV004730898	likely benign	NPHS2-related disorder	2019-04-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).