ClinVar Miner

Submissions for variant NM_153240.5(NPHP3):c.1928C>T (p.Pro643Leu)

gnomAD frequency: 0.00004  dbSNP: rs760831781
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797833 SCV002041837 likely pathogenic Nephronophthisis 3 2021-11-03 criteria provided, single submitter clinical testing Variant summary: NPHP3 c.1928C>T (p.Pro643Leu) 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 2.8e-05 in 250234 control chromosomes. c.1928C>T has been reported in the literature both as a compound heterozygous and a homozygous genotype respectively in at-least two individuals affected with Nephronopthisis type 3 from comprehensively genotyped cohorts undergoing whole exome/nephronopthisis-related disorder panel testing (example, Meng_2017, Mallett_2017). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001328312 SCV004268513 likely pathogenic Nephronophthisis 2023-05-14 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 not expected to disrupt NPHP3 protein function. ClinVar contains an entry for this variant (Variation ID: 988261). This missense change has been observed in individual(s) with nephronophthisis (PMID: 28844315, 28973083). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs760831781, gnomAD 0.005%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 643 of the NPHP3 protein (p.Pro643Leu).
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328312 SCV001449365 likely pathogenic Nephronophthisis 2012-07-28 no assertion criteria provided clinical testing This patient is homozygous for a variant in the NPHP3 gene (c.1928C>T). Homozygous or compound heterozygous mutations in NPHP3 are associated with Meckel syndrome type 7 (OMIM #267010), nephronophthisis type 3 (#604387) and renal-hepatic-pancreatic dysplasia type 1 (#208540). The c.1928C>T variant has not been previously reported in the literature or in the 1000 Genomes project or the ESP database. In silico analysis suggests that the substitution p.Pro643Leu is likely to be deleterious (AlignGVGD, SIFT, MutationTaster and PolyPhen2 through Alamut Visual v2.4). The proline is a highly conserved amino acid residue.

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