ClinVar Genomic variation as it relates to human health

The heterozygous p.Asp351ThrfsTer66 variant in EHMT1 was identified by our study in one individual with hypertelorism, hypotonia, large hands and feet, and global developmental delay (Broad Institute Rare Genomes Project). Trio genome analysis showed this variant to be de novo. The p.Asp351ThrfsTer66 variant in EHMT1 has not been previously reported in individuals with Kleefstra syndrome 1. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 351 and leads to a premature termination codon 66 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the EHMT1 gene is an established disease mechanism in autosomal dominant Kleefstra syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Kleefstra syndrome 1. ACMG/AMP Criteria applied: PVS1, PS2_Supporting, PM2_Supporting (Richards 2015).

The p.Asp351ThrfsX66 variant in EHMT1 has not been previously reported in individuals with Kleefstra syndrome and was absent from large population studies. However, trio whole genome sequencing confirmed this variant to be de novo in an individual with global developmental delay, hypotonia, and mild dysmorphic features by the Broad Institute Rare Genomes Project. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 351 and leads to a premature termination codon 66 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EHMT1 gene is an established disease mechanism in autosomal dominant Kleefstra syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Kleefstra syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting.