ClinVar Genomic variation as it relates to human health

This missense change has been observed in individual(s) with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 10878661). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 151 of the CLDN16 protein (p.Leu151Phe). ClinVar contains an entry for this variant (Variation ID: 5934). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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").

Across a selection of the available literature, the CLDN16 c.453G>T (p.Leu151Phe) missense variant has been identified in at least 28 individuals from more than 18 unrelated families with primary hypomagnesemia with hypercalciuria and nephrocalcinosis, including in a homozygous state in at least 18 individuals and in a compound heterozygous state in at least 10 individuals (Weber et al. 2000; Peco-Antić et al. 2010; Sikora et al. 2015). The variant was further identified in a heterozygous state in eight unaffected carrier parents (Weber et al. 2000). Two heterozygotes from one family had hypercalciuria but not primary hypomagnesemia (Tasic et al. 2005). The p.Leu151Phe variant was absent from 150 controls (Weber et al. 2000; Sikora et al. 2015) but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Genome Aggregation Database. Extended haplotype analysis suggests the p.Leu151Phe variant is likely a founder variant among patients originating from Germany or eastern European countries (Weber et al. 2000; Weber et al. 2001). Functional studies demonstrated that in transfected LLC-PK1 cells, the p.Leu151Phe variant led to partial function of the paracellin-1 protein compared to wild type (Hou et al. 2005). Based on the collective evidence, the p.Leu151Phe variant is classified as pathogenic for primary hypomagnesemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

A homozygous missense variant, NM_006580.3(CLDN16):c.453G>T, has been identified in exon 3 of 5 of the CLDN16 gene. The variant is predicted to result in a minor amino acid change from leucine to phenylalanine at position 151 of the protein (NP_006571.1(CLDN16):p.(Leu151Phe)). The leucine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within the Claudin superfamily domain. In silico predictions for this variant are consistently pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD database at a frequency of 0.007% (19 heterozygotes; 0 homozygotes). More than 33 homozygous CLDN16 p.(Leu151Phe) cases with Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) have been reported to date (ClinVar, OMIM, Weber, S. et al. (2000), Weber, S. et al. (2001), Konrad, M. et al. (2008), Li, H. et al. (2017)). The mutation is likely due to a founder effect in the European population (Weber, S. et al. (2001)). The homozygous variant has been reported to segregate with disease in 25 unrelated non-consanguinous families (Konrad, M. et al. (2008)). In addition, functional assays have shown >40% residual function of CLDN16 in cells expressing this variant, which corresponded with a later disease onset and slower progression of renal failure, compared to complete loss of function variants (Konrad, M. et al. (2008)). Alternate changes at residue 151 to tryptophan and proline have also been reported as pathogenic (ClinVar, Weber, S. et al. (2000), Konrad, M. et al. (2008)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.