ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.2335-1G>A (rs150038620)

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Total submissions: 9
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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 RCV000169038 SCV000698502 pathogenic Finnish congenital nephrotic syndrome 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The NPHS1 c.2335-1G>A variant involves the alteration of a conserved intronic nucleotide and 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts alterations to ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 7/121044 control chromosomes at a frequency of 0.0000578, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx RCV000599036 SCV000709982 pathogenic not provided 2018-03-09 criteria provided, single submitter clinical testing The c.2335-1G>A variant in the NPHS1 gene has been reported previously in multiple individuals with congenital nephrotic syndrome in the homozygous and compound heterozygous state with a second NPHS1 variant (Lenkkeri et al., 1999; Wong et al., 2013; Bierzynska et al., 2017). This splice site variant destroys the canonical splice acceptor site in intron 17. 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.2335-1G>A variant is observed in 24/126466 (0.019%) alleles from individuals of non-Finnish European background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.2335-1G>A as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000599036 SCV001151789 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000169038 SCV001194130 pathogenic Finnish congenital nephrotic syndrome 2019-12-20 criteria provided, single submitter clinical testing NM_004646.3(NPHS1):c.2335-1G>A is classified as pathogenic in the context of nephrotic syndrome, NPHS1-related. Sources cited for classification include the following: PMID 28117080, 23949594, 20507940 and 11854170. Classification of NM_004646.3(NPHS1):c.2335-1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000599036 SCV001217054 pathogenic not provided 2020-10-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 of the NPHS1 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 (rs150038620, ExAC 0.01%). This variant has been observed in several individuals affected with congenital nephrotic syndrome (PMID: 9915943, 28117080, 24902943, 11854170). ClinVar contains an entry for this variant (Variation ID: 188734). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000169038 SCV001427142 pathogenic Finnish congenital nephrotic syndrome 2018-09-17 criteria provided, single submitter clinical testing A heterozygous canonical splice-site variant, NM_004646.3(NPHS1):c.2335-1G>A, has been identified in intron 17 of 28 of the NPHS1 gene. The variant is likely to cause a splice defect, resulting in an altered protein length. The nucleotide at this position has very high conservation (Phylop UCSC). This nucleotide substitution is predicted to cause aberrant splicing of the gene and may result in a truncated protein; further testing via RNA studies are required to confirm if splicing is altered. The variant is present in the gnomAD database at a frequency of 0.009% (24 heterozygotes and 0 homozygotes). The variant has been reported multiple times as homozygous in patients with nephrotic syndrome (Bierzynska A. et al. (2017), Wong W. et al. (2013), Koziell A. et al. (2002), ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000169038 SCV000536792 pathogenic Finnish congenital nephrotic syndrome 2016-06-23 no assertion criteria provided research
Gharavi Laboratory,Columbia University RCV000599036 SCV000809261 pathogenic not provided 2018-09-16 no assertion criteria provided research
Natera, Inc. RCV000169038 SCV001460530 pathogenic Finnish congenital nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing

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