Submissions for variant NM_004646.4(NPHS1):c.697A>G (p.Thr233Ala)

gnomAD frequency: 0.00270  dbSNP: rs35238405

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000248913	SCV000310584	benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000248913	SCV000614342	uncertain significance	not specified	2017-06-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000905150	SCV001049718	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000248913	SCV001737622	likely benign	not specified	2021-05-20	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.697A>G (p.Thr233Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 282828 control chromosomes, predominantly at a frequency of 0.0093 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 3 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. c.697A>G has been reported in the literature in individuals affected with end stage renal disease (Bonomo_2014). The report does not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000905150	SCV001790197	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in a case-control study in association with end-stage renal disease in both diabetic and non-diabetic African American individuals (Bonomo et al., 2014); Observed in homozygous state in two clinically unaffected adult relatives of individuals referred for genetic testing at GeneDx, however adult-onset of NPHS1-related disorders is possible; This variant is associated with the following publications: (PMID: 24948143)
Genome-Nilou Lab	RCV001272298	SCV001806032	likely benign	Finnish congenital nephrotic syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294149	SCV002587394	uncertain significance	Focal segmental glomerulosclerosis	2020-01-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272298	SCV001454170	uncertain significance	Finnish congenital nephrotic syndrome	2020-01-05	no assertion criteria provided	clinical testing