ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.271T>C (p.Phe91Leu) (rs201065230)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723456 SCV000229132 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000723456 SCV000576649 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing The F91L variant in the NPHP4 gene has been reported previously in a family with nephronophthisis and retinitis pigmentosa, and in an individual with nephronophthisis, however a second NPHP4 variant was not identified for these individuals (Hoefele et al., 2005). In addition, F91L was reported as a heterozygous variant in an individual with mesocardia and laterality defects (French et al., 2012). The F91L variant is observed in 95/41774 (0.23%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The F91L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. Functional studies showed F91L failed to rescue the foraging defect and affected localization of NPHP4, and was concluded to be a hypomorphic variant (Masyukova et al., 2011). We interpret F91L as a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000177288 SCV000713021 uncertain significance not specified 2017-03-30 criteria provided, single submitter clinical testing The p.Phe91Leu (NM_015102.3 c.271T>C) variant in NPHP4 has been reported in 2 Ca ucasian individuals with Nephronophthisis and 1 individual with mesocardia, thou gh none with a second pathogenic variant on the other allele (Hoefele 2005, Otto 2011, and French 2012). This variant has also been reported in ClinVar (Variati on ID#16995440). This variant has been identified in 0.23% (95/41,774) of Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs201065230). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Ani mal models in C. elegans suggest that this variant is may lead to partial loss o f function; however, it is unclear how this partial loss of function may lead to disease (Masyukova 2011). In summary, the clinical significance of the p.Phe91L eu variant is uncertain.
Fulgent Genetics,Fulgent Genetics RCV000764007 SCV000894959 uncertain significance Nephronophthisis 4; Senior-Loken syndrome 4 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001081496 SCV001002672 likely benign Nephronophthisis 2019-12-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001097312 SCV001253582 uncertain significance Nephronophthisis 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001097313 SCV001253583 uncertain significance Senior-Loken syndrome 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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