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

gnomAD frequency: 0.00109  dbSNP: rs201065230

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723456	SCV000229132	uncertain significance	not provided	2018-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000723456	SCV000576649	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: p.F91L (described as p.F83L) failed to rescue the foraging defect and affected localization of NPHP4 in C. elegans, and was concluded to be a hypomorphic variant (Masyukova et al., 2011); Reported in published literature as heterozygous in an individual with mesocardia and laterality defects (French et al., 2012); Reported in published literature as heterozygous in a family with nephronophthisis and retinitis pigmentosa and in unrelated individuals with nephronophthisis; however, a second NPHP4 variant was not identified for these individuals (Hoefele et al., 2005; Otto et al., 2011); Identified in the heterozygous state via multi-gene panel testing in a patient with nephronophthisis who was also found to have a second heterozygous missense variant, but phase was unknown (Stokman et al., 2018); This variant is associated with the following publications: (PMID: 21546380, 22550138, 23188109, 29974258, 21068128, 15776426)
Laboratory for Molecular Medicine, Mass General Brigham 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081496	SCV001002672	likely benign	Nephronophthisis	2024-01-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, 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.
Clinical Genetics, Academic Medical Center	RCV000723456	SCV001925866	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723456	SCV001926618	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723456	SCV001975554	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732745	SCV005349228	uncertain significance	NPHP4-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The NPHP4 c.271T>C variant is predicted to result in the amino acid substitution p.Phe91Leu. This variant has been reported in the heterozygous state in at least two different individuals with nephronophthisis; however, a second NPHP4 variant was not detected in these individuals (Hoefele et al. 2005. PubMed ID: 15776426; Otto et al. 2010. PubMed ID: 21068128). This variant was also described in a large cohort of individuals with retinal or optic nerve disorders (Dineiro et al. 2020. PubMed ID: 32483926, described as a variant of uncertain significance in Table S12) as well as in the compound heterozygous state in an individual with a suspected ciliopathy (Stokman et al. 2018. PubMed ID: 29974258, Table S1). This variant is reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.