Submissions for variant NM_014625.4(NPHS2):c.561G>A (p.Met187Ile)

dbSNP: rs1673966819

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001270722	SCV001451469	likely pathogenic	Nephrotic syndrome, type 2	2019-07-31	criteria provided, single submitter	clinical testing	The NPHS2 c.561G>A (p.Met187Ile) missense variant has been reported in two studies in which it was identified in a compound heterozygous state with a variant of uncertain significance in one individual with sporadic steroid-resistant nephrotic syndrome (SRNS) and in another individual affected with SRNS in unknown zygosity (Wang et al. 2017; Santín et al. 2018). The variant was absent from 360 control chromosomes and is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on absence from frequency databases, presence in affected individuals, detection in trans with a pathogenic variant in an affected individual, and application of the ACMG criteria, the p.Met187Ile variant is classified as likely pathogenic for steroid-resistant nephrotic syndrome.
Invitae	RCV002537738	SCV003455814	uncertain significance	not provided	2022-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 187 of the NPHS2 protein (p.Met187Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NPHS2-related conditions (PMID: 20947785, 28476686). ClinVar contains an entry for this variant (Variation ID: 989252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPHS2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155384	SCV003844927	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: NPHS2 c.561G>A (p.Met187Ile) results in a conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251102 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.561G>A has been reported in the literature in at-least one individual affected with focal segmental glomerulosclerosis (Santn_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 2. 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. One laboratory classified the variant as pathogenic/likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001270722	SCV004191566	likely pathogenic	Nephrotic syndrome, type 2	2023-02-03	criteria provided, single submitter	clinical testing