Submissions for variant NM_015102.5(NPHP4):c.1127C>T (p.Ser376Leu)

gnomAD frequency: 0.00024  dbSNP: rs372414566

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000270134	SCV000342672	uncertain significance	not provided	2016-06-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000401015	SCV000358539	uncertain significance	Senior-Loken syndrome 4	2018-01-12	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	RCV000298117	SCV000358540	uncertain significance	Nephronophthisis 4	2018-01-12	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.
Invitae	RCV001859680	SCV002113504	uncertain significance	Nephronophthisis	2022-04-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 376 of the NPHP4 protein (p.Ser376Leu). This variant is present in population databases (rs372414566, gnomAD 0.09%). 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: 288535). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics	RCV002487256	SCV002789123	uncertain significance	Nephronophthisis 4; Senior-Loken syndrome 4	2022-02-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409417	SCV004112862	uncertain significance	NPHP4-related condition	2023-09-15	criteria provided, single submitter	clinical testing	The NPHP4 c.1127C>T variant is predicted to result in the amino acid substitution p.Ser376Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.096% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-5993382-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.