Submissions for variant NM_017780.4(CHD7):c.6079C>T (p.Arg2027Ter)

dbSNP: rs886040995

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000258088	SCV000328344	pathogenic	CHARGE syndrome	2016-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000330520	SCV000329270	pathogenic	not provided	2020-12-31	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Approximately 45% of CHD7 pathogenic variants are nonsense changes (Janssen et al., 2012; Zentner et al, 2010); This variant is associated with the following publications: (PMID: 27061523, 29300383, 25525159, 16155193, 22461308, 21158681, 23333604, 32625235, 31827275)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000258088	SCV000755717	pathogenic	CHARGE syndrome	2020-11-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). This variant has been reported de novo in individuals affected with CHARGE (PMID: 16155193, 22461308, 27061523). ClinVar contains an entry for this variant (Variation ID: 267435). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg2027*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000258088	SCV000786713	pathogenic	CHARGE syndrome		criteria provided, single submitter	research	The heterozygous p.Arg227Ter variant was identified by our study in one individual with CHARGE syndrome. The p.Arg227Ter variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000258088	SCV001244805	pathogenic	CHARGE syndrome	2018-04-26	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_017780.3(CHD7):c.6079C>T, has been identified in exon 30 of 38 in the CHD7 gene. The variant is predicted to result in a premature stop codon at position 2027 of the protein, NP_060250.2(CHD7):p.(Arg2027*). The variant is predicted to result in loss of protein function either through truncation (downstream functional domains would be affected) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G) and has been previously described as pathogenic in multiple individuals with CHARGE syndrome (ClinVar, Jongmans et al., (2016), Busa et al., (2016)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
DASA	RCV000258088	SCV002061227	pathogenic	CHARGE syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The c.6079C>T;p.(Arg2027*) variant creates a premature translational stop signal in the CHD7 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 267435; PMID: 16155193; 27061523; 29300383) - PS4. This variant is not present in population databases (rs886040995, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 16155193, 27061523, 29300383) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000330520	SCV005197487	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School	RCV000258088	SCV000680052	pathogenic	CHARGE syndrome	2017-10-27	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000258088	SCV001197958	likely pathogenic	CHARGE syndrome		no assertion criteria provided	research