ClinVar

Description

Variant summary: DONSON c.1466A>C (p.Lys489Thr) results in a non-conservative amino acid change in 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 0.00097 in 251470 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in DONSON causing Microcephaly, Short Stature, And Limb Abnormalities, allowing no conclusion about variant significance. c.1466A>C has been reported in the literature in individuals affected with Microcephaly, Short Stature, And Limb Abnormalities (Chong_2015, Reynolds_2017). In addition, this variant was found in a haplotype defined by 3 co-segregating variants (c.82A>C:p.Ser28Arg; c.78633A>G; c.1466A>C:p.Lys489Thr) (Reynolds_2017). These reports do not provide unequivocal conclusions about association of the variant with Microcephaly, Short Stature, And Limb Abnormalities. At least one publication reports experimental evidence evaluating an impact on protein function (Reynolds_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27040692, 28191891). ClinVar contains an entry for this variant (Variation ID: 431445). Based on the evidence outlined above, the variant was classified as uncertain significance.