ClinVar

Description

Variant summary: SETD2 c.19C>T (p.Gln7X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Pathogenic loss-of-function variants in SETD2 have been reported in the literature (PMID: 26084711, 24852293). However, there is a second in-frame ATG codon (at Met 12) downstream from the variant of interest, with an appropriate context (i.e. Kozak consensus) for translational initiation that could generate an N-terminally truncated protein product (with the loss of 11 N-terminal amino acids). The variant allele was found at a frequency of 4.8e-05 in 125046 control chromosomes (gnomAD), predominantly reported in the Latino subpopulation with a frequency of 0.00054 (i.e. 5/9314 alleles). c.19C>T has been reported in the literature in an individual affected with autism spectrum disorder (ASD), however, this patient had normal nonverbal intelligence (with no information on head circumference), and also was noted to carry a de novo 16p11.2 duplication (O'Roak_2012). Therefore this report does not provide unequivocal conclusions about association of the variant with Luscan-Lumish syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) or uncertain significance (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.