ClinVar Genomic variation as it relates to human health

Previously reported pathogenic nonsense variant reported in 16 patients (PMID: 11854170) with additional cases reported in literature.

The NPHS1 c.3478C>T (p.Arg1160Ter) variant is a stop-gained variant that is predicted to result in an absent or truncated protein product. Across a selection of the available literature, this variant has been identified in a homozygous state in 25 individuals with congenital nephrotic syndrome and in a presumed homozygous state in four additional cases (Koziell et al. 2002; Ovunc et al. 2012; Lenkkeri et al. 2013; Lovric et al. 2014; Cil et al. 2015; Amr et al. 2020; Wong et al. 2021). It has been proposed as a founder variant in Malta and has also been reported in a presumed compound heterozygous state with another stop-gained variant in one individual and in a confirmed compound heterozygous state with the p.Tyr977Cys variant in four affected siblings (Ovunc et al. 2012; Wang et al. 2017). Some individuals with this variant presented with slow disease progression. The p.Arg1160Ter variant is reported at a frequency of 0.000392 in the South Asian population of the Genome Aggregation Database (version 2.1.1). Functional studies conducted in HEK293 cells showed that the truncated protein resulting from this variant does not interact with podocin and failed to be recruited by podocin into lipid rafts at the plasma membrane (Huber et al. 2003). Based on the collective evidence, the p.Arg1160Ter variant is classified as pathogenic for congenital nephrotic syndrome.

This sequence change creates a premature translational stop signal (p.Arg1160*) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs267606919, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with NPHS1-related conditions (PMID: 9915943, 16518627, 24742477, 24902943, 25720465, 28204945). ClinVar contains an entry for this variant (Variation ID: 6873). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The observed stop gained c.3478C>T(p.Arg1160Ter) variant in NPHS1 gene has been reported in homozygous or compound heterozygous state in individual(s) affected with nephrotic syndrome (Koziell A, et. al., 2002; Cil O, et. al., 2015; Wang F, et. al.,2017). Functional studies conducted in HEK293 cells showed that the truncated protein resulting from this variant does not interact with podocin and failed to be recruited by podocin into lipid rafts at the plasma membrane (Huber TB, et. al., 2003). This variant is present with an allele frequency of 0.01% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predicts conflicting evidence on protein structure and function for this variant. The nucleotide change c.3478C>T in NPHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: The NPHS1 c.3478C>T (p.Arg1160X) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Nonsense mutations nearby to this variant have been classified as pathogenic by our laboratory previously (e.g., c.3325C>T [p.Arg1109X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts in the literature at a frequency of 0.000074 (9/121544 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Numerous publications have found the variant among patient cohorts as a homozygous genotype. In particular, the variant appears to be a founder mutation in Maltese individuals, where a study showed that of 50 non-Finnish patients analyzed, 12 were homozygous for the variant, 9 of which were from Malta (Koziell_HMG_2002). Additionally, a functional study showed that the variant prevents recruitment of nephrin (the protein product of NPHS1) into the lipid raft at the plasma membrane, which is important for many cellular processes, such as polarized sorting of membrane proteins and signal transduction (Huber_HMG_2003). In addition, one reputable database has classified this variant as pathogenic, though the last evaluation was in 2002. Taken together, this variant is classified as pathogenic.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006873 / PMID: 9915943). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

PVS1,PM2_p,PM3,PP4

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32779909, 34859019, 24742477, 24498843, 25525159, 28204945, 16518627, 31456999, 32363171, 34426522, 33565430, 31589614, 32860008, 32604935, 35064937, 36245711, 9915943, 29127259, 33980730, 37204080, 35755072)

This individual is heterozygous for a pathogenic variant, c.3478C>T, in the NPHS1 gene. This variant creates a premature stop codon p.(Arg1160*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.01% (25 out of 246,216 alleles). The c.3478C>T p.(Arg1160*) variant has been reported in several patients from India and Malta origin with the mild congenital nephrotic syndrome of Finnish type (CNF, Koziell et al 2002 Hum Mol Genet 11: 379-388; Heeringa et al 2008 Nephrol Dial Translplant 23: 3527-3533; Machuca et al 2010 J Am Soc Nephrol 21: 1209-1217; Wang et al 2016; HK J Paediatr 21: 294-297). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PVS1, PM2, PM3).