ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.3250dup (p.Val1084fs) (rs386833935)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483335 SCV000568763 pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The c.3250dupG variant in the NPHS1 gene, denoted also as nt3250insG due to alternative nomenclature, has been reported previously in the compound heterozygous state in individuals with congential nephrotic syndrome (Kestila et al., 1998; Lee et al., 2009; Wong et al., 2013). The c.3250dupG variant causes a frameshift starting with codon Valine1084, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Val1084GlyfsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3250dupG variant is observed in 2/6756 (0.03%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.3250dupG as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000049910 SCV000917910 pathogenic Finnish congenital nephrotic syndrome 2018-06-08 criteria provided, single submitter clinical testing Variant summary: NPHS1 c.3250dupG (p.Val1084GlyfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00023 in 82306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00023 vs 0.0034), allowing no conclusion about variant significance. c.3250dupG has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g. Heeringa 2008, Sadowski 2015). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000483335 SCV000964243 pathogenic not provided 2019-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1084Glyfs*12) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs386833936, ExAC 0.03%). This variant has been observed in several individuals affected with nephrotic Syndrome (PMID: 9660941, 19194555, 23949594, 28392951). ClinVar contains an entry for this variant (Variation ID: 56497). Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049910 SCV000082319 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000049910 SCV001132442 pathogenic Finnish congenital nephrotic syndrome 2017-02-09 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000049910 SCV001132803 pathogenic Finnish congenital nephrotic syndrome 2019-01-29 no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000049910 SCV001192689 pathogenic Finnish congenital nephrotic syndrome 2019-03-26 no assertion criteria provided clinical testing

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