ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.3478C>T (p.Arg1160Ter) (rs267606919)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000007276 SCV000693894 pathogenic Finnish congenital nephrotic syndrome 2017-06-25 criteria provided, single submitter research Previously reported pathogenic nonsense variant reported in 16 patients (PMID: 11854170) with additional cases reported in literature.
Integrated Genetics/Laboratory Corporation of America RCV000007276 SCV000698507 pathogenic Finnish congenital nephrotic syndrome 2017-04-17 criteria provided, single submitter clinical testing Variant summary: The NPHS1 c.3478C>T (p.Arg1160X) 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. Nonsense mutations nearby to this variant have been classified as pathogenic by our laboratory previously (e.g., c.3325C>T [p.Arg1109X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts in the literature at a frequency of 0.000074 (9/121544 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Numerous publications have found the variant among patient cohorts as a homozygous genotype. In particular, the variant appears to be a founder mutation in Maltese individuals, where a study showed that of 50 non-Finnish patients analyzed, 12 were homozygous for the variant, 9 of which were from Malta (Koziell_HMG_2002). Additionally, a functional study showed that the variant prevents recruitment of nephrin (the protein product of NPHS1) into the lipid raft at the plasma membrane, which is important for many cellular processes, such as polarized sorting of membrane proteins and signal transduction (Huber_HMG_2003). In addition, one reputable database has classified this variant as pathogenic, though the last evaluation was in 2002. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000007276 SCV000893522 pathogenic Finnish congenital nephrotic syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000808977 SCV000949111 pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1160*) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs267606919, ExAC 0.02%). This variant has been observed in several individuals and families affected with NPHS1-related conditions (PMID: 25720465, 9915943, 24742477, 28204945, 24902943, 16518627). ClinVar contains an entry for this variant (Variation ID: 6873). 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.
Baylor Genetics RCV000007276 SCV001163801 pathogenic Finnish congenital nephrotic syndrome criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197141 SCV001367777 pathogenic Nephrotic syndrome 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3. This variant was detected in heterozygous state.
Centogene AG - the Rare Disease Company RCV000007276 SCV001426582 pathogenic Finnish congenital nephrotic syndrome criteria provided, single submitter clinical testing
OMIM RCV000007276 SCV000027472 pathogenic Finnish congenital nephrotic syndrome 2002-02-15 no assertion criteria provided literature only
Counsyl RCV000007276 SCV000678051 pathogenic Finnish congenital nephrotic syndrome 2014-01-02 no assertion criteria provided clinical testing

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