ClinVar Miner

Submissions for variant NM_014625.4(NPHS2):c.467dup (p.Leu156fs)

dbSNP: rs528833893
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673011 SCV000798175 pathogenic Nephrotic syndrome, type 2 2018-02-27 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000673011 SCV000845598 uncertain significance Nephrotic syndrome, type 2 2018-08-07 criteria provided, single submitter clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000673011 SCV000891537 pathogenic Nephrotic syndrome, type 2 2017-12-30 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000673011 SCV000919902 pathogenic Nephrotic syndrome, type 2 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The NPHS2 c.467dupT (p.Leu156PhefsX11) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 42/199282 control chromosomes at a frequency of 0.0002108, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). This variant has been reported in multiple patients with steroid-resistant nephrotic syndrome and classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000673011 SCV001150183 pathogenic Nephrotic syndrome, type 2 2019-05-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001069505 SCV001234675 pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu156Phefs*11) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123). 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 steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis (PMID: 11729243, 19674119, 25903641, 28204945). ClinVar contains an entry for this variant (Variation ID: 556941). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001069505 SCV001988396 uncertain significance not provided 2020-06-26 criteria provided, single submitter clinical testing 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: 28780565, 28204945, 19674119, 25903641, 15338398, 11729243, 15059485, 30295827, 31209189, 33428103)
Revvity Omics, Revvity RCV000673011 SCV002018362 pathogenic Nephrotic syndrome, type 2 2020-10-07 criteria provided, single submitter clinical testing
3billion RCV000673011 SCV002521001 pathogenic Nephrotic syndrome, type 2 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with NPHS2 related disorder (ClinVar ID: VCV000556941 / PMID: 11729243). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV000673011 SCV004191532 pathogenic Nephrotic syndrome, type 2 2024-02-21 criteria provided, single submitter clinical testing
Precision Medicine Center, Zhengzhou University RCV000673011 SCV004218443 pathogenic Nephrotic syndrome, type 2 2023-12-01 criteria provided, single submitter clinical testing PVS1,PM2_p,PP4
Neuberg Centre For Genomic Medicine, NCGM RCV000673011 SCV005042599 pathogenic Nephrotic syndrome, type 2 criteria provided, single submitter clinical testing The frameshift c.467dup p.Leu156PhefsTer11 variant in NPHS2 gene has been reported previously in both homozygous and compound heterozygous state in individuals affected with nephrotic syndrome Wang et al. 2017; Shi et al. 2021. The p.Leu156PhefsTer11 variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic multiple submissions. This variant causes a frameshift starting with codon Leucine 156, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Leu156PhefsTer11. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001273619 SCV001456819 pathogenic Steroid-resistant nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004748896 SCV005360305 pathogenic NPHS2-related disorder 2024-05-13 no assertion criteria provided clinical testing The NPHS2 c.467dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu156Phefs*11). This variant was reported in multiple individuals with autosomal recessive nephrotic syndrome (Caridi et al. 2001. PubMed ID: 11729243; Klaassen et al. 2015. PubMed ID: 25903641; Saeed et al. 2021. PubMed ID: 33565430; Table S1, Zhu et al. 2022. PubMed ID: 35755072). This variant is reported in 0.057% of alleles in individuals of African descent in gnomAD. Frameshift variants in NPHS2 are expected to be pathogenic. This variant is interpreted as pathogenic.

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