ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.3481+1G>T

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV001192699 SCV001360990 pathogenic Finnish congenital nephrotic syndrome 2019-05-17 criteria provided, single submitter clinical testing Variant summary: NPHS1 c.3481+1G>T 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: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251448 control chromosomes (gnomAD). c.3481+1G>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome (Beltcheva_2001, Wong_2013, Kari_2014, Schoeb_2010, Hines_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001192699 SCV001427143 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.3481+1G>T, has been identified in intron 27 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 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 0.003% (3 heterozygotes and 0 homozygotes), and has been reported multiple times in patients with nephrotic syndrome (Bierzynska A. et al. (2017), Wong W. et al. (2013), Schoeb D. et al. (2010)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

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