Submissions for variant NM_017780.4(CHD7):c.2839C>T (p.Arg947Ter)

dbSNP: rs200220845

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000385062	SCV000331344	pathogenic	not provided	2013-02-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763186	SCV000893786	pathogenic	CHARGE association; Hypogonadotropic hypogonadism 5 with or without anosmia	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000385062	SCV001819634	pathogenic	not provided	2021-02-22	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); This variant is associated with the following publications: (PMID: 16615981, 25525159, 32804436, 32978145, 30287924, 24979395, 28475860, 18445044)
Revvity Omics, Revvity	RCV000385062	SCV002019270	pathogenic	not provided	2021-10-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155070	SCV003844699	pathogenic	CHARGE association	2023-02-02	criteria provided, single submitter	clinical testing	Variant summary: CHD7 c.2839C>T (p.Arg947X) 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, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248812 control chromosomes (gnomAD). c.2839C>T has been reported in the literature in multiple individuals affected with CHARGE Syndrome, including several cases where it has been confirmed to be a de novo occurrence (e.g. Aramaki_2006, Wincent_2008, Janssen_2012, Green_2014, Hale_2016, Wei_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV003155070	SCV004295214	pathogenic	CHARGE association	2023-03-01	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with CHARGE syndrome (PMID: 16615981, 33142350). ClinVar contains an entry for this variant (Variation ID: 95781). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg947*) 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).