Submissions for variant NM_015102.5(NPHP4):c.2965G>A (p.Glu989Lys)

gnomAD frequency: 0.00068  dbSNP: rs116606479

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723970	SCV000227833	uncertain significance	not provided	2018-03-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000367814	SCV000358444	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	RCV001093746	SCV000358445	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.
GeneDx	RCV000723970	SCV000581752	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	Identified in a patient with a clinical diagnosis of Senior-Loken syndrome, in cis with another missense allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32865313)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000261619	SCV000636142	likely benign	Nephronophthisis	2024-01-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001093746	SCV003836173	uncertain significance	Nephronophthisis 4	2022-01-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537396	SCV004747022	uncertain significance	NPHP4-related disorder	2023-12-30	criteria provided, single submitter	clinical testing	The NPHP4 c.2965G>A variant is predicted to result in the amino acid substitution p.Glu989Lys. This variant along with two other NPHP4 variants (c.2951C>T, p.Thr984Met and c.2203C>T, p.Arg735Trp) were reported in an individual with Senior–Løken syndrome (Sallum et al. 2020. PubMed ID: 32865313). This variant was also reported as uncertain significance with c.2203C>T (p.Arg735Trp) in individuals with chronic kidney disease and nephronophthisis (Al-Hamed et al. 2022. PubMed ID: 36177613; Tables S2 and S3, König et al. 2022. PubMed ID: 36090483). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000261619	SCV001449367	uncertain significance	Nephronophthisis	2018-07-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000723970	SCV001551007	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NPHP4 p.Glu989Lys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs116606479), ClinVar (classified as a VUS by Invitae, EGL Genetics, GeneDx and Illumina), and in LOVD 3.0 (variant is listed as likely benign). The variant was also identified in control databases in 125 of 280094 chromosomes at a frequency of 0.000446 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 50 of 24192 chromosomes (freq: 0.002067), Other in 8 of 7136 chromosomes (freq: 0.001121), South Asian in 17 of 30602 chromosomes (freq: 0.000556), Latino in 17 of 35368 chromosomes (freq: 0.000481), European (non-Finnish) in 31 of 128312 chromosomes (freq: 0.000242) and East Asian in 2 of 19532 chromosomes (freq: 0.000102), but not in the Ashkenazi Jewish, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu989 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723970	SCV001963102	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723970	SCV001972597	uncertain significance	not provided		no assertion criteria provided	clinical testing