Submissions for variant NM_015102.5(NPHP4):c.1228C>T (p.Gln410Ter)

gnomAD frequency: 0.00001  dbSNP: rs1237376396

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223028	SCV001395157	pathogenic	Nephronophthisis	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln410*) in the NPHP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHP4 are known to be pathogenic (PMID: 12205563, 23559409). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with nephronophthisis-related ciliopathies and dextrocardia (PMID: 23559409). ClinVar contains an entry for this variant (Variation ID: 951173). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV004809537	SCV005432505	pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	NPHP4: PVS1, PM2, PM3
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001223028	SCV001449370	pathogenic	Nephronophthisis	2018-05-30	no assertion criteria provided	clinical testing	This patient is heterozygous for a known variant, c.1228C>T, in the NPHP4 gene. This variant creates a premature stop codon (p.Gln410*), and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been previously reported as a compound heterozygote, with another pathogenic variant, in a patient with a nephronophthisis-related ciliopathy (Halbritter et al 2013 Hum Genet 132:865-884). This variant is considered to be pathogenic according to the ACMG guidelines.