Submissions for variant NM_017780.4(CHD7):c.7803C>G (p.Tyr2601Ter)

dbSNP: rs1563669432

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203728	SCV001374904	pathogenic	CHARGE syndrome	2019-09-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr2601*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. This nonsense change has been observed in individual(s) with CHARGE syndrome and/or congenital heart defects (PMID: 26785492, 28991257, 29300383, 18445044). In at least one individual the nonsense change was observed to be de novo. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001262014	SCV001439381	pathogenic	not provided	2020-09-23	criteria provided, single submitter	research	ACMG codes:PVS1, PS2, PM2
Lifecell International Pvt. Ltd	RCV001203728	SCV003921117	likely pathogenic	CHARGE syndrome		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.7803C>G in Exon 35 of the CHD7 gene that results in the amino acid substitution p.Tyr2601* was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 935187). The observed variant previously been reported in the patient affected with CHARGE syndrome (Nykamp K et. al 2017). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.