ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169038 SCV000220196 likely pathogenic Finnish congenital nephrotic syndrome 2014-03-27 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America 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
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

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