Submissions for variant NM_015102.5(NPHP4):c.2531C>T (p.Pro844Leu)

gnomAD frequency: 0.00042  dbSNP: rs186014615

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000271097	SCV000358468	uncertain significance	Senior-Loken syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001093853	SCV000358469	uncertain significance	Nephronophthisis 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000596475	SCV000703012	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing
Invitae	RCV000326128	SCV001227896	uncertain significance	Nephronophthisis	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 844 of the NPHP4 protein (p.Pro844Leu). This variant is present in population databases (rs186014615, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with NPHP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 297805). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHP4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003417959	SCV004113173	uncertain significance	NPHP4-related condition	2023-01-26	criteria provided, single submitter	clinical testing	The NPHP4 c.2531C>T variant is predicted to result in the amino acid substitution p.Pro844Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-5940254-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.