ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 677 of the NPHP1 protein (p.Glu677Gln). This variant is present in population databases (rs780427871, gnomAD 0.2%). This missense change has been observed in individual(s) with nephronophthisis and Bardet-Biedl syndrome (PMID: 27491411, 28624958). ClinVar contains an entry for this variant (Variation ID: 216416). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: NPHP1 c.2029G>C (p.Glu677Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251488 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHP1 causing Joubert Syndrome And Related Disorders (0.00056), suggesting that the variant may be a benign polymorphism found primarily in populations of East Asian origin. c.2029G>C has been reported in the literature in the heterozygous state in settings of WES and multigene panel testing primarily in East Asian individuals affected with disorders related to Joubert syndrome, including retinitis pigmentosa and nephronophthisis, without strong evidence for causality (e.g. Fu_2013, Katagiri_2014, Sugimoto_2016, Kang_2016, Mori_2017, Qi_2017, Luo_2020). These report(s) do 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

The c.2029G>C (p.E677Q) alteration is located in exon 20 (coding exon 20) of the NPHP1 gene. This alteration results from a G to C substitution at nucleotide position 2029, causing the glutamic acid (E) at amino acid position 677 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.