ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.313G>A (p.Asp105Asn)

gnomAD frequency: 0.00001  dbSNP: rs386833932
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049906 SCV000793653 likely pathogenic Finnish congenital nephrotic syndrome 2017-08-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049906 SCV000919900 likely pathogenic Finnish congenital nephrotic syndrome 2018-11-02 criteria provided, single submitter clinical testing Variant summary: NPHS1 c.313G>A (p.Asp105Asn) results in a conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-06 in 275106 control chromosomes (gnomAD and publications). The variant, c.313G>A, has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (Sadowski_2014, Sako_2005, Sen_2017). 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. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002513693 SCV003443152 likely pathogenic not provided 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 105 of the NPHS1 protein (p.Asp105Asn). 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 missense change has been observed in individuals with nephrotic syndrome (PMID: 25349199, 28204945; Invitae). ClinVar contains an entry for this variant (Variation ID: 56493). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049906 SCV000082315 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000049906 SCV002087110 likely pathogenic Finnish congenital nephrotic syndrome 2020-11-04 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002294009 SCV002587470 uncertain significance Kidney disorder 2016-12-12 flagged submission clinical testing

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