ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.563A>T (p.Asn188Ile) (rs145125791)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000353631 SCV000333820 benign not specified 2015-08-30 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000353631 SCV000614340 likely benign not specified 2016-09-30 criteria provided, single submitter clinical testing
Counsyl RCV000665656 SCV000789811 likely benign Finnish congenital nephrotic syndrome 2017-02-22 criteria provided, single submitter clinical testing
Invitae RCV000958774 SCV001105647 benign not provided 2020-12-08 criteria provided, single submitter clinical testing
Mendelics RCV000665656 SCV001141051 likely benign Finnish congenital nephrotic syndrome 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001125723 SCV001284825 uncertain significance Congenital nephrotic syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Nilou-Genome Lab RCV000665656 SCV001653371 likely benign Finnish congenital nephrotic syndrome 2021-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000353631 SCV001737736 benign not specified 2021-06-11 criteria provided, single submitter clinical testing Variant summary: NPHS1 c.563A>T (p.Asn188Ile) results in a non-conservative amino acid change located in the CD80-like, immunoglobulin C2-set domain (IPR013162) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.006 in 251492 control chromosomes, predominantly at a frequency of 0.0093 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.563A>T has been reported in the literature in individuals affected with a variety of renal phenotypes such as congenital FSGS (example Koziell_2002), Alport syndrome (example, Gibson_2013, Chatterjee_2013) and in settings of multigene panel testing for pediatric Nephrotic syndrome (example Abid_2018). In families with this variant, a clear lack of segregation of this variant with the underlying clinical phenotype of Alport syndrome attributed to a causative variant in the COL4A5 gene was noted (example, Gibson_2013, Chatterjee_2013). Multiple reports of co-occurrences with other pathogenic variant(s) have been reported (homozygous NPHS2 (436)delA, in two siblings with FSGS, Koziell_2002; COL4A5 c.973G>A, p.Gly325Arg, Gibson_2013; COL4A5 c.3482G>A, p.Gly1161Glu, Chatterjee_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing a predominant classification of likely benign (n=4)/benign (n=2), VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.

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