Submissions for variant NM_017780.4(CHD7):c.7252C>T (p.Arg2418Ter)

dbSNP: rs587783455

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145690	SCV000192797	pathogenic	CHARGE syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000145690	SCV000631275	pathogenic	CHARGE syndrome	2022-08-20	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with CHARGE syndrome (PMID: 16155193, 21158681, 21554267, 22462537). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 158314). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2418*) 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	RCV000760307	SCV000890159	pathogenic	not provided	2022-05-05	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: 26928066, 21554267, 22462537, 21158681, 16155193, 32410215, 25525159)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001999	SCV001159814	pathogenic	not specified	2018-07-09	criteria provided, single submitter	clinical testing	The CHD7 c.7252C>T p.Arg2418Ter variant (rs587783455) is reported in the literature in multiple individuals affected with CHARGE syndrome (Bartels 2010, Husu 2013, Jongmans 2006, Pauli 2012). In one affected individual, parental testing for the variant suggested a de novo origin (Bartels 2010). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 158314). It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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. Based on available information, this variant is considered to be 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. Husu E et al. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome. Clin Genet. 2013 Feb;83(2):125-34. Jongmans MC et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006 Apr;43(4):306-14 Pauli S et al. CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin Genet. 2012 Mar;81(3):234-9.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000760307	SCV001334396	pathogenic	not provided	2019-06-26	criteria provided, single submitter	clinical testing
3billion	RCV000145690	SCV002521088	pathogenic	CHARGE syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported as pathogenic more than twice with clinical assertions and evidence for the classification (ClinVar ID: VCV000158314). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.