ClinVar Miner

Submissions for variant NM_144696.6(AXDND1):c.3032-21A>T (rs775006954)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517167 SCV000614352 pathogenic not provided 2016-12-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000761450 SCV000699385 pathogenic Idiopathic nephrotic syndrome 2017-02-10 criteria provided, single submitter clinical testing Variant summary: The NPHS2 c.779T>A (p.Val260Glu) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a medium size and polar Glutamine (Q) located in the Band 7 domain of the protein(InterPro). 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 2/121340 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). It was reported in several nephrotic syndrome patients in homozygosity indicating causality. Moreover, in at least one family, the variant co-segregated with the disease in multiple family members further supporting a pathogenic outcome. A functional study demonstrated the variant to impair localization of NPHS2 to the plasma member ant to result accumulation of the variant in ER accumulation. Taken together, this variant is classified as pathogenic.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761450 SCV000891536 uncertain significance Idiopathic nephrotic syndrome 2017-12-30 criteria provided, single submitter curation
Invitae RCV000517167 SCV001213285 pathogenic not provided 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces valine with glutamic acid at codon 260 of the NPHS2 protein (p.Val260Glu). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is present in population databases (rs775006954, ExAC 0.02%). This variant has been observed in individual(s) with nephrotic syndrome (PMID: 15253708, 28658201). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447882). This variant has been reported to affect NPHS2 protein function (PMID: 14675423). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000761450 SCV001451468 pathogenic Idiopathic nephrotic syndrome 2019-07-31 criteria provided, single submitter clinical testing The NPHS2 c.779T>A (p.Val260Glu) variant is a missense variant that has been reported in at least four studies, in which it is found in at least 23 individuals with steroid-resistant nephrotic syndrome, 20 of whom were unrelated. The variant was found in a homozygous state in at least 19 individuals and in a compound heterozygous state with a frameshift variant in another individual (Machuca et al. 2010; Kari et al. 2013; Guaragna et al. 2015; Asharam et al. 2018). The p.Val260Glu variant was found in a heterozygous state in one of 72 controls and is reported at a frequency of 0.000321 in the African population of the Genome Aggregation Database (Asharam et al. 2018). Functional analysis of the p.Val260Glu variant protein in HEK293 cells demonstrated the variant results in retention of podocin in the endoplasmic reticulum in contrast to localization of the wild type protein at the plasma membrane demonstrating a trafficking defect (Roselli et al. 2004). Based on the presence of the variant in affected individuals, functional evidence supporting gene impact, low allele frequency in public frequency databases, and in silico prediction data, the p.Val260Glu variant is classified as pathogenic for steroid-resistant nephrotic syndrome.
Counsyl RCV000761450 SCV001132443 pathogenic Idiopathic nephrotic syndrome 2018-12-17 no assertion criteria provided clinical testing
Natera, Inc. RCV001273612 SCV001456812 pathogenic Steroid-resistant nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing

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