Submissions for variant NM_014625.4(NPHS2):c.862G>A (p.Ala288Thr)

dbSNP: rs1490010141

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672271	SCV000797362	likely pathogenic	Nephrotic syndrome, type 2	2018-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001702831	SCV002245844	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 288 of the NPHS2 protein (p.Ala288Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of steroid-resistant nephrotic syndrome (PMID: 12464671, 19145239, 21415313, 24509478). It has been reported in trans with the variant p.Arg229Gln in related affected individuals. This suggests that the combination of p.Arg229Gln and this variant may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 556281). 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%. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 24509478). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001702831	SCV002756570	uncertain significance	not provided	2022-05-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21415313, 29660491, 24509478, 25349199, 20947785, 30260545, Behnam2016[paper], 24072147, 33102883, 15253708, 19145239, 12464671)
Baylor Genetics	RCV000672271	SCV004191574	pathogenic	Nephrotic syndrome, type 2	2022-07-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702831	SCV001927724	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702831	SCV001952969	likely pathogenic	not provided		no assertion criteria provided	clinical testing