ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.121_122del (p.Leu41fs) (rs386833873)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000049844 SCV000698495 pathogenic Finnish congenital nephrotic syndrome 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is a Finnish founder mutation known as Fin-major. The variant of interest has been found in the large, broad control population, ExAC, with an allele frequency of 114/113010, predominantly in the Finnish cohort, 80/5484, which is expected since the variant is indicated to be a Finnish founder mutation. The variant of interest has been reported in multiple affected individuals as homozygous and compound heterozygous. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Gharavi Laboratory,Columbia University RCV000681697 SCV000809146 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Invitae RCV000681697 SCV000931674 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu41Aspfs*50) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs386833873, ExAC 1.5%). This variant has been observed in many individuals with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941, 9915943). This variant is also known as "Fin major" in the literature. ClinVar contains an entry for this variant (Variation ID: 56431). Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000049844 SCV000027465 pathogenic Finnish congenital nephrotic syndrome 1998-03-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049844 SCV000082253 pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Pathogenic.
Blueprint Genetics RCV000049844 SCV000207134 pathogenic Finnish congenital nephrotic syndrome 2014-10-17 no assertion criteria provided clinical testing
Counsyl RCV000049844 SCV000485240 pathogenic Finnish congenital nephrotic syndrome 2016-02-29 no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000049844 SCV001142487 pathogenic Finnish congenital nephrotic syndrome 2020-01-06 no assertion criteria provided curation NM_004646.3:c.121_122delCT in the NPHS1 gene is also known as Fin-major in publications. It has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant locates at the 2nd exon out of 29 exons of the biological transcript of NPHS1. It results in a premature termination codon, predicting to cause a truncated or absent NPHS1 protein due to nonsense mediated decay. Lenkkeri et al reported one American congenital Nephrotic Syndrome patient was a heterozygote for the Fin-major mutation, carrying a single base insertion in exon 24 of the other allele (PMID: 9915943). This variant also has been observed in many individuals with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941; 9915943). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PS4; PM3; PP4.

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