Submissions for variant NM_014625.4(NPHS2):c.868G>A (p.Val290Met)

gnomAD frequency: 0.00011  dbSNP: rs200482683

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190610	SCV000245644	likely pathogenic	Nephrotic syndrome, type 2	2014-05-12	criteria provided, single submitter	clinical testing	The p.Val290Met variant in NPHS2 has been reported in at least 5 individuals with steroid-resistant nephrotic syndrome. Two individuals were homozygous for this variant (Reiterova 2012, Kerti 2013) and three were compound heterozygotes (Karle 2002, Skalova 2010, Kerti 2013). The variant has been identified in 0.012% (1/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2) do not provide strong support for or against an impact to the protein. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000190610	SCV000699386	pathogenic	Nephrotic syndrome, type 2	2016-11-10	criteria provided, single submitter	clinical testing	Variant summary: The NPHS2 c.868G>A (p.Val290Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 9/114830 control chromosomes at a frequency of 0.0000784, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). This variant has been reported in numerous patients with NSPH2. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000190610	SCV000893930	likely pathogenic	Nephrotic syndrome, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000190610	SCV000914365	pathogenic	Nephrotic syndrome, type 2	2019-01-11	criteria provided, single submitter	clinical testing	The NPHS2 c.868G>A (p.Val290Met) missense variant is reported in six studies in which it is found in a total of 11 individuals affected with steroid-resistant nephrotic syndrome, including in five individuals in a compound heterozygous state, in three affected individuals in a homozygous state and in three individuals in a heterozygous state (Karle et al. 2002; Skálová et al. 2010; Reiterová et al. 2012; Kerti et al. 2013; Lipska et al. 2013; Bińczak-Kuleta et al. 2014). The p.Val290Met variant was absent from 700 control chromosomes and is reported at a frequency of 0.0002412 in the European (non-Finnish) population of the Genome Aggregation Database. Although this variant has been observed in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Based on the collective evidence, the p.Val290Met variant is classified as pathogenic for steroid-resistant nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Genetics, Inc.	RCV000190610	SCV001193774	pathogenic	Nephrotic syndrome, type 2	2019-12-20	criteria provided, single submitter	clinical testing	NM_014625.2(NPHS2):c.868G>A(V290M) is classified as pathogenic in the context of NPHS2-related nephrotic syndrome. Sources cited for classification include the following: PMID 18216321, 23242530, 21171529, 17899208, 22578956, 11805166 and 14978175. Classification of NM_014625.2(NPHS2):c.868G>A(V290M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000681842	SCV001246104	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681842	SCV001581817	pathogenic	not provided	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 290 of the NPHS2 protein (p.Val290Met). This variant is present in population databases (rs200482683, gnomAD 0.03%). This missense change has been observed in individual(s) with NPHS2-related disease (PMID: 11805166, 21171529, 23242530, 24856380, 30295827). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 126418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000190610	SCV003817460	likely pathogenic	Nephrotic syndrome, type 2	2022-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000681842	SCV003930256	likely pathogenic	not provided	2024-07-19	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 21171529, 33565430, 11805166, 26211502, 24742477, 30295827, 31980526, 30647093, 24856380, 23645318, 23242530, 18216321, 17899208, 14978175, Smirnova2023[abstract], 32129207, 36938085, 30586318, 38170106, 36898413)
PreventionGenetics, part of Exact Sciences	RCV003398709	SCV004119857	pathogenic	NPHS2-related disorder	2022-12-19	criteria provided, single submitter	clinical testing	The NPHS2 c.868G>A variant is predicted to result in the amino acid substitution p.Val290Met. This variant has been reported in the compound heterozygous and homozygous state in individuals with NPHS2-related disease (see for example - Karle et al. 2002. PubMed ID: 11805166; Skálová et al. 2010. PubMed ID: 21171529; Kerti et al. 2012. PubMed ID: 23242530; Table S7 - Groopman et al. 2018. PubMed ID: 30586318; Schapiro et al. 2019. PubMed ID: 30295827; Yao et al. 2019. PubMed ID: 30647093). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-179521743-C-T). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000190610	SCV004191524	pathogenic	Nephrotic syndrome, type 2	2024-03-27	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000190610	SCV005090988	pathogenic	Nephrotic syndrome, type 2	2024-04-15	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PP3, PP5- The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 126418). Low frequency in gnomAD population databases. It has been previously reported as causative for steroid-resistant nephrotic syndrome (PMID: 11805166, 21171529)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000190610	SCV005397116	pathogenic	Nephrotic syndrome, type 2	2024-10-30	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM2,PP3; Identified as compound heterozygous with NM_014625.4:c.948del
OMIM	RCV000114358	SCV000147970	risk factor	Nephrotic syndrome, type 2, susceptibility to	2013-05-01	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000681842	SCV000809319	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000190610	SCV001469192	pathogenic	Nephrotic syndrome, type 2	2020-09-10	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000681842	SCV001809323	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000681842	SCV001966468	likely pathogenic	not provided		no assertion criteria provided	clinical testing