Submissions for variant NM_001170629.2(CHD8):c.4846G>C (p.Asp1616His)

gnomAD frequency: 0.00001  dbSNP: rs1055883888

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
New York Genome Center	RCV001263370	SCV001441412	uncertain significance	Autism; Intellectual disability	2020-03-19	criteria provided, single submitter	clinical testing	The c.4846G>C (p.Asp1616His) variant detected in the CHD8 gene substitutes a well conserved Aspartic Acid for Histidine at amino acid 1616/2582 (coding exon 26/38).This variant is present with low frequency in gnomAD (1 heterozygote, 0 homozygotes; allele frequency: 3.19e-5) suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score: -5.09) and Damaging (SIFT; score:0.005) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Asp1616 residue is not within a mapped domain of CHD8 (UniProkKB: Q9HCK8). Given the lack of compelling evidence for its pathogenicity, the c.4846G>C (p.Asp1616His) variant detected in the CHD8 gene is reported here as a Variant of Uncertain Significance.
GeneDx	RCV001566846	SCV001790428	uncertain significance	not provided	2020-08-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge