ClinVar Genomic variation as it relates to human health

The FGFR3 c.1537G>A; p.Asp513Asn variant (rs121913112) is reported in the literature in a family affected with lacrimo-auriculo-dento-digital syndrome (Rohmann 2006). This variant co-segregated with disease in this family and was not observed in either parent of the oldest affected individual, suggesting a de novo origin (Rohmann 2006). This variant is found in the general population with an overall allele frequency of 0.005% (13/281908 alleles) in the Genome Aggregation Database. The aspartate at codon 513 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Asp513Asn variant is uncertain at this time. References: Rohmann E et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006 Apr;38(4):414-7.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 17682060, 19215249, 28483234, 16501574)

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 513 of the FGFR3 protein (p.Asp513Asn). This variant is present in population databases (rs121913112, gnomAD 0.009%). This missense change has been observed in individual(s) with lacrimo-auriculo-dento-digital syndrome (PMID: 16501574). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

Variant summary: FGFR3 c.1537G>A (p.Asp513Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250540 control chromosomes. This frequency does not allow conclusions about variant significance. c.1537G>A has been reported in the literature as a reportedly de-novo variant in an affected father and two of his offspring affected with features of Lacrimo-auriculo-dento-digital (LADD) syndrome (example, Rohmann_2006 cited in Ryu_2020). To our knowledge, it has not been reported in the literature in individuals affected with Achondroplasia. These data indicate that the variant may be associated with disease although the frequency in control cohorts seems at odds with the reportedly de-novo inheritance in the family ascertained above (Rohmann_2006). 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 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.