ClinVar Miner

Submissions for variant NM_014625.4(NPHS2):c.873+2T>A

gnomAD frequency: 0.00001  dbSNP: rs967339926
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668232 SCV000792803 likely pathogenic Nephrotic syndrome, type 2 2017-07-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001051658 SCV001215826 pathogenic not provided 2020-05-06 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed to be homozygous or in combination with another NPHS2 variant in individuals affected with nephrotic syndrome (PMID: 24509478, 26668027, 23645318, 14978175). ClinVar contains an entry for this variant (Variation ID: 552884). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in the last intron (intron 7) of the NPHS2 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668232 SCV001360831 pathogenic Nephrotic syndrome, type 2 2021-05-21 criteria provided, single submitter clinical testing Variant summary: NPHS2 c.873+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 5-prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249820 control chromosomes. c.873+2T>A has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 2 (e.g. Ruff_2004, Buscher_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000668232 SCV004049253 likely pathogenic Nephrotic syndrome, type 2 2023-04-11 criteria provided, single submitter clinical testing

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