ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.2663+2T>G (rs762392183)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586590 SCV000698503 likely pathogenic Finnish congenital nephrotic syndrome 2016-10-17 criteria provided, single submitter clinical testing Variant summary: The NPHS1 c.2663+2T>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 in silico prediction tools via alamut predict the complete loss of a 3' splicing donor site. This variant is absent in 70534 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Athena Diagnostics Inc RCV000712428 SCV000842921 pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV000586590 SCV001163802 pathogenic Finnish congenital nephrotic syndrome criteria provided, single submitter clinical testing
Invitae RCV000712428 SCV001382068 likely pathogenic not provided 2019-09-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the NPHS1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NPHS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000586590 SCV000790006 likely pathogenic Finnish congenital nephrotic syndrome 2017-03-14 no assertion criteria provided clinical testing

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