ClinVar Miner

Submissions for variant NM_153240.5(NPHP3):c.2342G>A (p.Gly781Asp)

gnomAD frequency: 0.00005  dbSNP: rs781180515
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Johns Hopkins Genomics, Johns Hopkins University RCV000855408 SCV000998470 likely pathogenic NPHP3-related Meckel-like syndrome 2019-08-16 criteria provided, single submitter clinical testing InterpretationThis NPHP3 variant was previously identified in trans with a second likely disease-causing variant in two siblings presenting with severe multiorgan polycystic disease. This variant (rs781180515) is rare (<0.1%) in a large population dataset (gnomAD: 1/251358 total alleles; 0.0003978%; no homozygotes). Of three bioinformatics tools queried, two predict that the substitution would be probably damaging while the third predicts that it would be neutral. The glycine residue at this position is evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this missense variant may have a possible effect on normal exon 17 splicing, although this has not been confirmed experimentally to our knowledge. This variant is likely pathogenic in this patient.
Invitae RCV001858521 SCV002308565 likely pathogenic Nephronophthisis 2023-02-14 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 781 of the NPHP3 protein (p.Gly781Asp). This variant is present in population databases (rs781180515, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of nephronophthisis (PMID: 24776604). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 693990). 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 NPHP3 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265903 SCV002547703 uncertain significance not specified 2022-05-21 criteria provided, single submitter clinical testing Variant summary: NPHP3 c.2342G>A (p.Gly781Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251358 control chromosomes. c.2342G>A has been reported in the literature as a compound heterozygous genotype in at-least two siblings affected with neonatal onset multiorgan polycystic disease, a rare neonatal ciliopathy presentation of NPHP3 (example, Leeman_2014). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Both submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272374 SCV002557899 likely pathogenic Nephronophthisis 3 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid (exon 17). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as likely pathogenic in ClinVar and in two siblings with neonatal onset multiorgan polycystic disease (PMID: 24776604). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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