Submissions for variant NM_017780.4(CHD7):c.7891C>T (p.Arg2631Ter)

dbSNP: rs587783457

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145696	SCV000192804	pathogenic	CHARGE syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000317612	SCV000329273	pathogenic	not provided	2025-02-19	criteria provided, single submitter	clinical testing	Has also been reported in a patient with features of congenital hypogonadotropic hypogonadism (PMID: 37108593); 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26666243, 25525159, 32804436, 37108593, 21158681)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000145696	SCV000631277	pathogenic	CHARGE syndrome	2019-11-11	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 observed in individual(s) with clinical features of CHARGE syndrome (PMID: 26666243, 21158681). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg2631*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000317612	SCV001474368	pathogenic	not provided	2019-07-24	criteria provided, single submitter	clinical testing	The CHD7 c.7891C>T; p.Arg2631Ter variant (rs587783457) is reported in the medical literature in several individuals with CHARGE syndrome (Bartels 2010). The variant is reported in the ClinVar database (Variation ID: 158320) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Bartels CF et al. Mutations in the CHD7 gene: the experience of a commercial laboratory. Genet Test Mol Biomarkers. 2010 Dec;14(6):881-91.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000145696	SCV002320814	pathogenic	CHARGE syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700463	SCV005203497	pathogenic	Hypogonadotropic hypogonadism 5 with or without anosmia	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: CHD7 c.7891C>T (p.Arg2631X) 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. The variant was absent in 244614 control chromosomes. c.7891C>T has been reported in the literature as heterozygous genotype in multiple individuals affected with clinical features of CHARGE syndrome (Bartels_2010, Lim_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21158681, 26666243). ClinVar contains an entry for this variant (Variation ID: 158320). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000145696	SCV005374779	pathogenic	CHARGE syndrome		criteria provided, single submitter	clinical testing	The observed stop gained variant c.7891C>T(p.Arg2631Ter) in the CHD7 gene has been reported previously in multiple individuals affected with clinical features of CHARGE syndrome (Bartels CF, et al., 2010; Lim EC, et al., 2015). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic by multiple submitters. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000317612	SCV005433660	pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	CHD7: PVS1, PM2, PS2:Moderate, PS4:Moderate
PreventionGenetics, part of Exact Sciences	RCV003407563	SCV004115564	pathogenic	CHD7-related disorder	2024-07-25	no assertion criteria provided	clinical testing	The CHD7 c.7891C>T variant is predicted to result in premature protein termination (p.Arg2631*). This variant has been reported in multiple individuals with CHARGE syndrome (Bartels et al. 2010. PubMed ID: 21158681; Wei et al. 2020. PubMed ID: 32804436). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHD7 are expected to be pathogenic. This variant is interpreted as pathogenic.