ClinVar

Description

Variant summary: MKKS c.830T>C (p.Leu277Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome (6.4e-05 vs 0.00076), allowing no conclusion about variant significance. c.830T>C has been reported in the literature in both compound heterozygous and homozygous individuals affected with Bardet-Biedl Syndrome and has been reported to segregate with disease in related individuals (e.g., Katsanis_2000, Pereiro_2011, Groopman_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant behaved a a null allele in a zebrafish model of gastrulation phenotypes (Zaghloul_2010) and greatly disrupted MKKS protein interactions (e.g., Rachel_2012, Seo_1010). Five ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; four submitters classified the variant as pathogenic/likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.