ClinVar

Description

Variant summary: ASXL1 c.3677T>A (p.Leu1226Gln) 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 4e-05 in 249774 control chromosomes and was found in at least 10 heterozygous individuals without severe, early-onset conditions (gnomAD). Predominantly, de-novo truncating variants in ASXL1 have been reported in association with autosomal dominant early-onset Bohring-Opitz syndrome or as somatic alterations in individuals of advanced age. Therefore, while these data are suggestive of a benign role for this variant, a definitive conclusion about variant significance cannot be drawn at this time. To our knowledge, no occurrence of c.3677T>A in individuals affected with Bohring-Opitz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.