Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000205615 | SCV000261757 | pathogenic | Nephronophthisis | 2019-12-22 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 19 of the NPHP3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs751527253, ExAC 0.05%). This variant has been reported to segregate with Meckel-Gruber-like syndrome and embryonic lethality in families (PMID: 18371931, 20007846). This variant has also been observed in several individuals affected with a nephronophthisis-related ciliopathy (PMID: 26673778, 23559409). ClinVar contains an entry for this variant (Variation ID: 220868). An experimental study has shown that this variant results in altered splicing, likely by usage of a cryptic splice site, resulting in a prematurely truncated protein (PMID: 20007846). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NPHP3 are known to be pathogenic (PMID: 23559409). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000355185 | SCV000329431 | pathogenic | not provided | 2015-09-08 | criteria provided, single submitter | clinical testing | The maternally inherited c.2694-2_2694-1delAG mutation in the NPHP3 gene has been reported previously in association with a Meckel-Gruber-like syndrome in two siblings who had this mutation in the homozygous state (Bergmann et al., 2008). This splice site mutation destroys the canonical splice acceptor site in intron 19. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2694-2_2694-1delAG mutation was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. We interpret c.2694-2_2694-1delAG as a disease-causing mutation. |
Broad Institute Rare Disease Group, |
RCV000055628 | SCV000693903 | pathogenic | Renal-hepatic-pancreatic dysplasia 1 | 2017-06-25 | criteria provided, single submitter | research | |
EGL Genetic Diagnostics, |
RCV000355185 | SCV000706826 | pathogenic | not provided | 2017-03-15 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV000002753 | SCV001369566 | pathogenic | Meckel syndrome type 7 | 2019-08-12 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2. |
Molecular Biology Laboratory, |
RCV000593585 | SCV001425113 | pathogenic | Nephronophthisis 3 | 2020-02-01 | criteria provided, single submitter | research | |
OMIM | RCV000002753 | SCV000022911 | pathogenic | Meckel syndrome type 7 | 2010-01-01 | no assertion criteria provided | literature only | |
OMIM | RCV000055628 | SCV000083853 | pathogenic | Renal-hepatic-pancreatic dysplasia 1 | 2010-01-01 | no assertion criteria provided | literature only | |
Developmental Genetics Unit, |
RCV000256425 | SCV000322802 | pathogenic | Polycystic kidney disease | no assertion criteria provided | research | ||
Gharavi Laboratory, |
RCV000355185 | SCV000809211 | likely pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
Broad Institute Rare Disease Group, |
RCV000593585 | SCV000924491 | pathogenic | Nephronophthisis 3 | 2018-06-15 | no assertion criteria provided | research | The heterozygous c.2694-2_2694-1delAG variant was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nephronophthisis. This variant is pathogenic based off of multiple reports in ClinVar and the literature. |