ClinVar Genomic variation as it relates to human health

This variant was found once in our laboratory In trans with a frameshift variant (C185fs) in a 2-year-old female with mild global delays, aortic coarctation, polydactyly, sublingual cysts. This patient has since been reported (PMID:25427950). Heterozygotes would be expected to be asymptomatic carriers.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital heart defects, hamartomas of tongue, and polysyndactyly (MIM#217085). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. Additionally, this variant affects the last nucleotide of exon 2, and is predicted to disrupt RNA splicing. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 36 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. Although this variant has been reported as a variant of uncertain significance by clinical laboratories in ClinVar it has also been reported in three unrelated compound heterozygous individuals with a consistent ciliopathy phenotype (PMID: 33046855, PMID: 27158779, PMID: 25427950). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Reduction of protein expression has been shown in Xenopus embryos, however the functional assay was not quantitative so it was deemed to be insufficient evidence to determine the effect on the protein (PMID: 27158779). (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The WDPCP c.160G>A (p.Asp54Asn) variant has been reported in two studies and found in two patients with ciliopathy phenotypes in a compound heterozygous state with truncating variants and in two unaffected family members in a heterozygous state (Saari et al. 2015; Toriyama et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of a WDPCP construct with the p.Asp54Asn variant in Xenopus embryos demonstrated reduced protein expression compared to wild type protein, indicating that the variant may disrupt protein stability (Toriyama et al. 2016). Based on the evidence, the p.Asp54Asn variant is classified as a variant of unknown significance but suspicous for pathogenicty for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 54 of the WDPCP protein (p.Asp54Asn). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200322968, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of WDPCP-related conditions (PMID: 25427950, 28289185). ClinVar contains an entry for this variant (Variation ID: 162669). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on WDPCP function (PMID: 27158779). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

The WDPCP c.160G>A variant is predicted to result in the amino acid substitution p.Asp54Asn. This variant is the last nucleotide of exon 2 and is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant has been reported in the compound heterozygous state in two individuals who presented with polydactyly, tongue hamartomas, and/or coarctation of the aorta (Saari et al. 2015. PubMed ID: 25427950; Toriyama et al. 2016. PubMed ID: 27158779). It has also been reported as heterozygous in an individual with obesity and BMI between 35.00 and 39.99 (Savas et al. 2019. PubMed ID: 31216558). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.