ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.3250dup (p.Val1084fs)

dbSNP: rs386833935
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483335 SCV000568763 pathogenic not provided 2024-06-19 criteria provided, single submitter clinical testing Identified with a second NPHS1 variant, either phase unknown or confirmed on the opposite allele (in trans) in multiple unrelated patients with congenital nephrotic syndrome referred for genetic testing at GeneDx and in the literature (PMID: 9660941, 23949594, 19194555); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23949594, 9660941, 19194555)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000483335 SCV000964243 pathogenic not provided 2024-01-08 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. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 9660941, 19194555, 23949594, 28392951). ClinVar contains an entry for this variant (Variation ID: 56497). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000049910 SCV002018357 pathogenic Finnish congenital nephrotic syndrome 2022-05-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000049910 SCV002778711 pathogenic Finnish congenital nephrotic syndrome 2021-07-07 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000049910 SCV003935873 likely pathogenic Finnish congenital nephrotic syndrome 2020-04-20 criteria provided, single submitter clinical testing
Baylor Genetics RCV000049910 SCV004191377 pathogenic Finnish congenital nephrotic syndrome 2024-03-29 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000049910 SCV005042862 likely pathogenic Finnish congenital nephrotic syndrome criteria provided, single submitter clinical testing The frameshift variant c.3250dup p.Val1084GlyfsTer12 in the NPHS1 gene has been reported previously in a heterozygous state in individuals affected with Congenital Nephrotic Syndrome and Steroid-Resistant Nephrotic Syndrome SRNS Bullich et al., 2015; Nguyen et al., 2017. This variant is reported with the allele frequency 0.007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000049910 SCV005086564 pathogenic Finnish congenital nephrotic syndrome 2024-09-20 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome type 1 (MIM# 256300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 and v3: 25 heterozygotes, 0 homozygotes. (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in multiple unrelated individuals. This variant has been reported in multiple individuals with nephrotic syndrome (PMID: 35102923, 19194555, 22653594, 28392951, 25407002, ClinVar, LOVD). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Gly796Glu)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000049910 SCV000027468 pathogenic Finnish congenital nephrotic syndrome 1998-03-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049910 SCV000082319 likely pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission from probable-pathogenic to Likely pathogenic.
Counsyl RCV000049910 SCV001132442 pathogenic Finnish congenital nephrotic syndrome 2017-02-09 no assertion criteria provided clinical testing This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328317 SCV001449376 pathogenic Nephrotic syndrome 2018-08-28 no assertion criteria provided clinical testing This patient is also heterozygous for a known pathogenic variant, c.3250dup, in the NPHS1 gene. This frameshifting variant (dbSNP: rs386833936) is predicted to create a premature stop codon 11 positions downstream (p.Val1084Glyfs*12), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in patients with congenital nephrotic syndrome of Finnish type in the literature (Kestila et al 1998 Mol Cell 1:575-582; Lenkkeri et al 1999 Am J Hum Genet 64:51-61; Lee et al 2009 J Korean Med Sci 24:S210-S214).
Natera, Inc. RCV000049910 SCV001456411 pathogenic Finnish congenital nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000483335 SCV001930595 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000483335 SCV001965082 pathogenic not provided no assertion criteria provided clinical testing
Yale Center for Mendelian Genomics, Yale University RCV001328317 SCV002106880 likely pathogenic Nephrotic syndrome 2017-11-10 no assertion criteria provided literature only

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