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

Total submissions: 10

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.