Submissions for variant NM_004646.4(NPHS1):c.3562G>A (p.Ala1188Thr)

gnomAD frequency: 0.00177  dbSNP: rs116700257

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669816	SCV000794604	benign	Finnish congenital nephrotic syndrome	2017-10-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712431	SCV000842924	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000712431	SCV001040801	likely benign	not provided	2024-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000712431	SCV001815008	likely benign	not provided	2020-10-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28117080)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282307	SCV002570783	likely benign	not specified	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.3562G>A (p.Ala1188Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 252492 control chromosomes (gnomAD and Bonomo_2014), predominantly at a frequency of 0.0058 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 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3562G>A has been reported in the literature in at least one heterozygous individual affected with Nephrotic Syndrome, without strong evidence for causality (e.g. Bierzynska_2017) and therefore this report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as benign (n=1)/likely benign (n=2), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Vasylyeva lab, Texas Tech University Health Sciences Center	RCV000669816	SCV004123135	benign	Finnish congenital nephrotic syndrome	2017-10-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907931	SCV004718341	likely benign	NPHS1-related disorder	2020-10-27	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).