ClinVar Miner

Submissions for variant NM_153240.5(NPHP3):c.2694-2_2694-1del (rs751527253)

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Total submissions: 10
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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.
GeneDx 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,Broad Institute RCV000055628 SCV000693903 pathogenic Renal-hepatic-pancreatic dysplasia 1 2017-06-25 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000355185 SCV000706826 pathogenic not provided 2017-03-15 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000256425 SCV001369566 pathogenic Polycystic kidney dysplasia 2019-08-12 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
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,King Faisal Specialist Hospital & Research Centre RCV000256425 SCV000322802 pathogenic Polycystic kidney dysplasia no assertion criteria provided research
Gharavi Laboratory,Columbia University RCV000355185 SCV000809211 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute 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.

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