Submissions for variant NM_014625.4(NPHS2):c.714G>C (p.Arg238Ser)

dbSNP: rs748812981

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248715	SCV001422221	likely pathogenic	not provided	2019-10-26	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant (c.714G>T (p.R238S)) giving rise to the same protein effect observed here (p.Arg238Ser) has been determined to be pathogenic (PMID: 15253708, 15264208, 16810518,23515051, 24072147). This suggests that this variant is also likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NPHS2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 238 of the NPHS2 protein (p.Arg238Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117865	SCV003801079	pathogenic	Idiopathic nephrotic syndrome	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: NPHS2 c.714G>C (p.Arg238Ser) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250728 control chromosomes. c.714G>C has not been reported in the literature but a different variant, c.714G>T also encoding p.Arg238Ser has been reported in the HGMD database. p.Arg238Ser has been reported in the literature as a biallelic homozygous and compound heterozygous genotype in multiple individuals affected with Steroid Resistant Nephrotic Syndrome, Type 2 (example, PMID: 14675423, 23515051). Therefore, ACMG PS1 criteria - same amino acid change as a previously established pathogenic variant regardless of nucleotide change has been engaged in this ascertainment. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV003346414	SCV004049266	likely pathogenic	Nephrotic syndrome, type 2	2023-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835346	SCV002090087	likely pathogenic	Steroid-resistant nephrotic syndrome	2021-05-20	no assertion criteria provided	clinical testing