Submissions for variant NM_015102.5(NPHP4):c.2029C>T (p.Pro677Ser)

dbSNP: rs547495754

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596610	SCV000704371	uncertain significance	not provided	2016-12-05	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002694	SCV001156395	pathogenic	Senior-Loken syndrome 4	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001416064	SCV001618234	likely benign	Nephronophthisis	2025-01-12	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002286526	SCV002574910	uncertain significance	Nephronophthisis 4	2022-08-08	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 16 of the NPHP4 gene (chr1:g.5904731G>A; Depth: 156x) that results in the amino acid substitution of Serine for Proline at codon 677 (p.Pro677Ser; ENST00000378156.9) was detected (Table). This variant has a minor allele frequency of 0.1%, 0.006% in the 1000 genomes, gnomAD . The in silico predictions# of the variant are probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to classified as variant of uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV002286526	SCV005329608	uncertain significance	Nephronophthisis 4	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.2029C>T(p.Pro677Ser) in the NPHP4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.05% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Uncertain significance/Likely benign. The amino acid Proline at position 677 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004732955	SCV005359951	likely benign	NPHP4-related disorder	2024-04-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).