Submissions for variant NM_017780.4(CHD7):c.4015C>T (p.Arg1339Ter)

dbSNP: rs1563644066

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727588	SCV000854835	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727588	SCV000883604	pathogenic	not provided	2017-05-04	criteria provided, single submitter	clinical testing	The CHD7 c.4015C>T; p.Arg1339Ter variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. This variant has been reported in individuals with CHARGE syndrome (Bergman 2012, Jongmans 2006, Lalani 2006), and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database). Taken together, this variant is considered pathogenic. REFERENCES Bergman JE et al. The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. J Clin Endocrinol Metab. 2012 May;97(5):E858-62. Jongmans MC et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006 Apr;43(4):306-14. Lalani SR et al. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet. 2006 Feb;78(2):303-14.
3billion	RCV001809789	SCV002058432	pathogenic	CHARGE syndrome	2022-01-03	criteria provided, single submitter	clinical testing	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 (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000592245). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID:16400610, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001809789	SCV003440856	pathogenic	CHARGE syndrome	2023-04-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 592245). This premature translational stop signal has been observed in individual(s) with clinical features of CHARGE syndrome and/or Kallman syndrome (PMID: 16400610, 22399515). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1339*) 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).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001809789	SCV003922259	pathogenic	CHARGE syndrome	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Arg1339Ter variant in CHD7 was identified by our study in one individual with seventh cranial nerve palsy. Trio exome analysis showed this variant to be de novo. The p.Arg1339Ter variant in CHD7 has been previously reported in at least 4 unrelated individuals with CHARGE syndrome (PMID: 16400610, PMID: 22399515, ClinVar SCV002058432.1). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 2 individuals with confirmed paternity and maternity (PMID: 16400610). This variant is assumed de novo in 1 individual, but maternity and paternity have not been confirmed (PMID: 22399515). This variant has also been reported in ClinVar (Variation ID: 592245) and has been interpreted as pathogenic by Eurofins NTD LLC, ARUP Laboratories, 3Billion, and Invitae. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1339, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CHD7 gene is an established disease mechanism in CHARGE syndrome. In summary, this variant meets criteria to be classified as pathogenic for CHARGE syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PM2_Supporting, PM6_Supporting (Richards 2015).
Clinical Immunology, Karolinska University Hospital	RCV001809789	SCV004031471	pathogenic	CHARGE syndrome	2023-06-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000727588	SCV005078048	pathogenic	not provided	2024-03-15	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16155193, 18445044, 16615981, 25525159, 16400610, 34894067, 24790386, 22399515)
Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University	RCV001809789	SCV003802713	association not found	CHARGE syndrome		no assertion criteria provided	clinical testing