Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000727324 | SCV000574424 | uncertain significance | not provided | 2017-04-01 | criteria provided, single submitter | clinical testing | The c.2171G>A variant in the NPHP3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.2171G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.2171G>A may decrease the natural splice donor site in exon 15. However, in the absence of RNA/functional studies, the actual effect of the c.2171G>A change in this individual is unknown. If c.2171G>A does not alter splicing, it will result in the R724N missense change. The R724N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.2171G>A as a variant of uncertain significance. |
| Eurofins Ntd Llc |
RCV000727324 | SCV000707559 | uncertain significance | not provided | 2017-04-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001851280 | SCV002308393 | uncertain significance | Nephronophthisis | 2022-09-01 | criteria provided, single submitter | clinical testing | This sequence change affects codon 724 of the NPHP3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NPHP3 protein. This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of nephronophthisis (PMID: 34013113). ClinVar contains an entry for this variant (Variation ID: 424601). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |