ClinVar Miner

Submissions for variant NM_153240.5(NPHP3):c.3494G>A (p.Arg1165Gln)

gnomAD frequency: 0.00001  dbSNP: rs138630766
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000343363 SCV000332188 uncertain significance not provided 2015-06-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553649 SCV001774584 uncertain significance not specified 2021-08-02 criteria provided, single submitter clinical testing Variant summary: NPHP3 c.3494G>A (p.Arg1165Gln) results in a conservative amino acid change located in the 8th tetratricopeptide repeat (IPR019734) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251184 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NPHP3 causing Joubert Syndrome and Related Disorders (0.0004), allowing no conclusion about variant significance. The variant, c.3494G>A has been reported in the literature in heterozygous form in a child affected with end-stage kidney disease (Tory_2009). This report does not provide unequivocal conclusions about association of the variant with Joubert Syndrome and Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001859546 SCV002191171 uncertain significance Nephronophthisis 2022-11-15 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 281413). 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) performed at Invitae indicates that this missense variant is not expected to disrupt NPHP3 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. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1165 of the NPHP3 protein (p.Arg1165Gln). This variant is present in population databases (rs138630766, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of nephronophthisis (PMID: 19177160).
Fulgent Genetics, Fulgent Genetics RCV002494815 SCV002799715 uncertain significance Renal-hepatic-pancreatic dysplasia 1; Nephronophthisis 3; NPHP3-related Meckel-like syndrome 2024-03-12 criteria provided, single submitter clinical testing
Eurofins-Biomnis RCV003236581 SCV003935079 likely pathogenic Nephronophthisis 3 2022-11-10 criteria provided, single submitter clinical testing

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