Submissions for variant NM_004646.4(NPHS1):c.319G>A (p.Ala107Thr)

gnomAD frequency: 0.00002  dbSNP: rs386833933

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000049907	SCV000914839	uncertain significance	Finnish congenital nephrotic syndrome	2018-11-03	criteria provided, single submitter	clinical testing	The NPHS1 c.319G>A (p.Ala107Thr) variant has been reported in a compound heterozygous state with a splice site variant in one individual with congenital Finnish nephrosis (Philippe et al. 2008). The p.Ala107Thr variant was absent from 188 control chromosomes, but is reported at a frequency of 0.000027 in the European (non-Finnish) population from the Genome Aggregation Database. Functional studies in HeLa cells demonstrated that the p.Ala107Thr variant protein localized to the plasma membrane with wild type nephrin. In HEK293 cells, co-immunoprecipitation studies showed that both nephrin homodimerization and NEPH1 heterodimerization were intact and unaffected by the p.Ala107Thr variant (Philippe et al. 2008). Based on the limited evidence, the p.Ala107Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001169934	SCV001251664	likely pathogenic	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000049907	SCV001760449	likely pathogenic	Finnish congenital nephrotic syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000049907	SCV002060102	uncertain significance	Finnish congenital nephrotic syndrome	2021-11-03	criteria provided, single submitter	clinical testing	NM_004646.3(NPHS1):c.319G>A(A107T) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. A107T has been observed in cases with relevant disease (PMID: 18614772, 20507940, 25349199). Functional assessments of this variant are available in the literature (PMID: 18614772). A107T has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_004646.3(NPHS1):c.319G>A(A107T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330420	SCV004039537	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.319G>A (p.Ala107Thr) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249074 control chromosomes (gnomAD). c.319G>A has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1, (Philippe_2008, Sadowski_2015), and one was reported as compound heterozygous with a (likely) pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18614772, 25349199). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001169934	SCV004297318	likely pathogenic	not provided	2024-03-17	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 107 of the NPHS1 protein (p.Ala107Thr). This variant is present in population databases (rs386833933, gnomAD 0.003%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 18614772, 25349199). 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: 56494). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. Experimental studies have shown that this missense change does not substantially affect NPHS1 function (PMID: 18614772). This variant disrupts the p.Ala107 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been observed in individuals with NPHS1-related conditions (PMID: 20172850, 20798252), which suggests that this may be a clinically significant amino acid residue. 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.
Baylor Genetics	RCV000049907	SCV005053652	likely pathogenic	Finnish congenital nephrotic syndrome	2024-02-23	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049907	SCV000082316	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.