ClinVar Miner

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

gnomAD frequency: 0.00026  dbSNP: rs751527253
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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205615 SCV000261757 pathogenic Nephronophthisis 2024-01-26 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 19 of the NPHP3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs751527253, gnomAD 0.05%). Disruption of this splice site has been observed in individual(s) with Meckel-Gruber-like syndrome and/or nephronophthisis-related ciliopathy (PMID: 18371931, 20007846, 23559409, 26673778). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220868). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20007846). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000355185 SCV000329431 pathogenic not provided 2022-05-03 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate this variant leads to loss of splice acceptor resulting in skipping of exon 20 (Molinari et al., 2018); This variant is associated with the following publications: (PMID: 27894351, 28973083, 30002499, 34426522, 32055034, 31980526, 32552793, 32901917, 20007846, 18371931, 33726816, 27535533)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000055628 SCV000693903 pathogenic Renal-hepatic-pancreatic dysplasia 1 2023-05-02 criteria provided, single submitter curation The heterozygous c.2694-2_2694-1del variant in NPHP3 was identified by our study in one individual with renal-hepatic-pancreatic dysplasia 1. Trio exome analysis showed this variant to be in trans with a likely pathogenic variant (ClinVar Variation ID: 635041). The c.2694-2_2694-1del variant in NPHP3 has been previously reported in 22 unrelated individuals with NPHP3-related disease (PMID: 33532864, PMID: 28973083, PMID: 32055034, PMID: 32552793, PMID: 32901917, PMID: 27894351, PMID: 33726816, PMID: 23559409, PMID: 26673778, PMID: 30002499, PMID: 33323469), but has been identified in 0.04% (14/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs963574014). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 22 previously reported unrelated individuals (PMID: 33532864, PMID: 28973083, PMID: 32055034, PMID: 32552793, PMID: 32901917, PMID: 27894351, PMID: 33726816, PMID: 23559409, PMID: 26673778, PMID: 30002499, PMID: 33323469), 12 were homozygotes (PMID: 32055034, PMID: 32552793, PMID: 27894351, PMID: 18371931, PMID: 20007846) and 4 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 33532864, ClinVar Variation ID: 659899; PMID: 28973083, ClinVar Variation ID: 988261; PMID: 23559409, ClinVar Variation ID: 96511, ClinVar Variation ID: 693989 ; PMID: 30002499, ClinVar Variation ID: 262696; PMID: 33323469, ClinVar Variation ID: 1454640), which increases the likelihood that the c.2694-2_2694-1del variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 220868) and has been interpreted as pathogenic by multiple submitters. RT-PCR analysis performed on affected tissue shows evidence of altered splicing of exon 20 (PMID: 32552793, PMID: 30002499, PMID: 20007846). A different nucleotide change that also results in a splice acceptor variant at the same site, c.2694-2A>T (ClinVar Variation ID: 1524627), has been previously reported likely pathogenic, and the variant being assessed here, c.2694-2_2694-1del, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 3' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 21 bases from the intron-exon boundary, providing evidence that this variant may delete 7 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the NPHP3 gene is an established disease mechanism in autosomal recessive renal-hepatic-pancreatic dysplasia 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive renal-hepatic-pancreatic dysplasia 1. ACMG/AMP Criteria applied: PVS1_Moderate, PS1_Supporting, PS3_Moderate, PM3_VeryStrong (Richards 2015).
Eurofins Ntd Llc (ga) RCV000355185 SCV000706826 pathogenic not provided 2017-03-15 criteria provided, single submitter clinical testing
Gharavi Laboratory, Columbia University RCV000355185 SCV000809211 likely pathogenic not provided 2018-09-16 criteria provided, single submitter research
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000002753 SCV001369566 pathogenic NPHP3-related Meckel-like syndrome 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, Fundació Puigvert RCV000593585 SCV001425113 pathogenic Nephronophthisis 3 2020-02-01 criteria provided, single submitter research
3billion RCV000593585 SCV002012327 pathogenic Nephronophthisis 3 2021-10-02 criteria provided, single submitter clinical testing Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0002759, PM2).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000220868.16). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics RCV000355185 SCV002501393 pathogenic not provided 2021-05-24 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000355185 SCV002544835 pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing NPHP3: PVS1, PS3:Supporting, PS4:Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000593585 SCV002766885 pathogenic Nephronophthisis 3 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Meckel syndrome 7 (MIM# 267010), nephronophthisis 3 (MIM# 604387) and renal-hepatic-pancreatic dysplasia 1 (MIM# 208540). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR done on whole blood RNA of an affected individual demonstrated exon 20 skipping, which is expected to result in a frameshift (PMID: 30002499). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 78 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3: 1 heterozygote, 0 homozygotes). (SB) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals described to have nephronophthisis, end stage renal disease or ciliopathy syndrome and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 28921755, 30002499, 32055034). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV002500658 SCV002810601 pathogenic Renal-hepatic-pancreatic dysplasia 1; Nephronophthisis 3; NPHP3-related Meckel-like syndrome 2021-12-21 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000002753 SCV004047650 pathogenic NPHP3-related Meckel-like syndrome criteria provided, single submitter clinical testing The splice site c.2694-2_2694-1del variant has been reported to segregate with Meckel syndrome and embryonic lethality in families (Bergmann et. al., 2008). 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 (Fiskerstrand et. al., 2010). The c.2694-2_2694-1del variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.02759% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005), and loss-of-function variants in NPHP3 are known to be pathogenic (Halbritter et. al., 2013). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. The same variant (c.2694-2_2694-1del) has been observed in her father.
PreventionGenetics, part of Exact Sciences RCV004530240 SCV004115080 pathogenic NPHP3-related disorder 2024-01-20 criteria provided, single submitter clinical testing The NPHP3 c.2694-2_2694-1delAG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with NPHP3 related disorders (Bergmann et al. 2008. PubMed ID: 18371931; Meng et al 2017. PubMed ID: 28973083; Shaheen et al 2016. PubMed ID: 27894351; Shamseldin et al. 2021. PubMed ID: 34645488). Expression assays reveal that this variant leads to skipping of exon 20 (Maddirevula et al. 2020. PubMed ID: 32552793). This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000593585 SCV004807901 pathogenic Nephronophthisis 3 2024-03-29 criteria provided, single submitter clinical testing
OMIM RCV000002753 SCV000022911 pathogenic NPHP3-related Meckel-like syndrome 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
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000256425 SCV000322802 pathogenic Polycystic kidney disease no assertion criteria provided research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000355185 SCV001742234 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000355185 SCV001806968 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000355185 SCV001967526 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000355185 SCV002037362 pathogenic not provided no assertion criteria provided clinical testing

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