Submissions for variant NM_017780.4(CHD7):c.7957C>T (p.Arg2653Ter)

dbSNP: rs587783458

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145697	SCV000192805	pathogenic	CHARGE syndrome	2013-09-24	criteria provided, single submitter	clinical testing
Invitae	RCV000145697	SCV000631279	pathogenic	CHARGE syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with clinical features of CHARGE syndrome (PMID: 16400610). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158321). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2653*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900).
GeneDx	RCV000578500	SCV000680504	pathogenic	not provided	2023-02-21	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 (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16400610, 26663670, 28726809, 29653002)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000145697	SCV000699440	pathogenic	CHARGE syndrome	2016-10-24	criteria provided, single submitter	clinical testing	Variant summary: The CHD7 c.7957C>T (p.Arg2653X) variant results in a premature termination codon, predicted to cause a truncated or absent CHD7 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.6070C>T, p.Arg2024X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 97562 control chromosomes and has been reported in multiple CHARGE patients in the literature. In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000145697	SCV000781112	pathogenic	CHARGE syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000145697	SCV001429600	pathogenic	CHARGE syndrome	2019-03-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266191	SCV001444363	pathogenic	Inborn genetic diseases	2018-02-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000578500	SCV002019268	pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000145697	SCV004046044	pathogenic	CHARGE syndrome		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 36 of 38 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change, including as de novo variant in patients with CHARGE syndrome (PMID: 26663670, 16400610). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.7957C>T (p.Arg2653Ter) variant is classified as Pathogenic.