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

gnomAD frequency: 0.00003  dbSNP: rs748812981

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672577	SCV000797691	likely pathogenic	Nephrotic syndrome, type 2	2018-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672577	SCV000919903	pathogenic	Nephrotic syndrome, type 2	2018-02-22	criteria provided, single submitter	clinical testing	Variant summary: NPHS2 c.714G>T (p.Arg238Ser) results in a non-conservative amino acid change located in the Band 7 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was identified in 4/276486 control chromosomes of the gnomAD dataset. This frequency is not significantly higher than expected for a pathogenic variant in NPHS2 causing Nephrotic Syndrome, Type 2 (1.4e-05 vs 1.80e-03), allowing no conclusion about variant significance. The c.714G>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 (Basiratnia_2013, Lipska_2013, Sadowski_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Roselli_2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000672577	SCV001548498	likely pathogenic	Nephrotic syndrome, type 2	2021-03-30	criteria provided, single submitter	clinical testing	NPHS2 c.714G>T has been identified in the compound heterozygote or homozygous state in multiple individuals with steroid-resistant nephrotic syndrome. This NPHS2 variant (rs748812981) is rare (<0.1%) in a large population dataset (gnomAD: 4/282142 total alleles; 0.0014%; no homozygotes). There is an entry for this variant in ClinVar (Variation ID: 556556). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across most species assessed. We consider NPHS2 c.714G>T to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382865	SCV001581818	pathogenic	not provided	2024-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 238 of the NPHS2 protein (p.Arg238Ser). This variant is present in population databases (rs748812981, gnomAD 0.004%). This missense change has been observed in individuals with steroid-resistant nephrotic syndrome (PMID: 1523708, 15264208, 23515051, 24072147). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556556). 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 expected to disrupt NPHS2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294366	SCV002587258	likely pathogenic	Focal segmental glomerulosclerosis	2022-09-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001382865	SCV002771012	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Fulgent Genetics, Fulgent Genetics	RCV000672577	SCV002798184	pathogenic	Nephrotic syndrome, type 2	2024-05-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000672577	SCV004049267	likely pathogenic	Nephrotic syndrome, type 2	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000672577	SCV004191537	pathogenic	Nephrotic syndrome, type 2	2024-03-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000672577	SCV004238315	likely pathogenic	Nephrotic syndrome, type 2	2023-06-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273614	SCV001456814	pathogenic	Steroid-resistant nephrotic syndrome	2020-09-16	no assertion criteria provided	clinical testing