ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.5405-17G>A

dbSNP: rs794727423
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000309868 SCV000228370 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing
GeneDx RCV000309868 SCV000329267 pathogenic not provided 2023-07-19 criteria provided, single submitter clinical testing Published functional studies show variant leads to an in-frame insertion of 5 amino acids in a non-repeat region (Vuorela et al., 2007; Legendre et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31965297, 18073582, 26411921, 22033296, 16155193, 26538304, 27321065, 14626219, 28492532, 29255276, 15666308, 31289371, 22539353, 23849776, 26544072, 26590800, 25472840, 17661815, 22461308, 21532573, 21378379, 20186815, 20130577, 17299439, 10590394, 16400610, 18834967, 29304373, 15300250, 31216405, 30176936, 32411386, 32326958, 35904121, 33502061, 36151134)
Invitae RCV000470769 SCV000552236 pathogenic CHARGE association 2023-12-08 criteria provided, single submitter clinical testing This sequence change falls in intron 25 of the CHD7 gene. It does not directly change the encoded amino acid sequence of the CHD7 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with CHARGE syndrome (PMID: 16155193, 22033296, 26538304, 26544072). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 195978). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratoire de Genetique Biologique, CHU de Poitiers RCV000470769 SCV000579495 pathogenic CHARGE association 2017-05-05 criteria provided, single submitter in vitro Found de novo on many CHARGE syndrome Patients. Minigene assays confirm the pathogenic effect on splicing mechanism
Ambry Genetics RCV000623964 SCV000742794 likely pathogenic Inborn genetic diseases 2016-03-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000850540 SCV000992749 pathogenic CHARGE association; Hypogonadotropic hypogonadism 5 with or without anosmia 2017-12-31 criteria provided, single submitter clinical testing
Center for Molecular Medicine, Children’s Hospital of Fudan University RCV000470769 SCV001190569 pathogenic CHARGE association 2019-05-10 criteria provided, single submitter clinical testing
3billion RCV000470769 SCV002318720 pathogenic CHARGE association 2022-03-22 criteria provided, single submitter clinical testing The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000195978) It has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 18073582, 16155193, 22033296, 26544072, 3bilion dataset). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SPLICEAI: 1.0>=0.8). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen RCV000309868 SCV002564004 pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing CHD7: PS2, PM2, PS3:Moderate, PS4:Moderate
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000470769 SCV002768847 pathogenic CHARGE association 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with CHARGE syndrome (MIM#214800) and hypogonadotropic hypogonadism 5 with or without anosmia (MIM#612370). The genotype-phenotype correlation is currently unestablished. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Although the variant does not lie within the splice site region of intron 25, a minigene assay demonstrated activation of a cryptic splice site. An inframe insertion of 5 amino acids was predicted (p.(His1801_Gly1802insAspGlyHisGlyThr)) (PMID: 29255276). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. However, it is important to note that these tools are not optimized for variants beyond the splice region. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Intron 25 has been described as a hotspot for intronic variants due to the presence of a distant splicing branch point (PMID: 29255276). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with CHARGE syndrome, several of whom were proven to be de novo for this variant (PMID: 29255276; ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis)]. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Athena Diagnostics Inc RCV000309868 SCV002817252 pathogenic not provided 2020-11-05 criteria provided, single submitter clinical testing This variant appears to occur de novo in a patient tested at Athena Diagnostics and in previously reported individuals with CHARGE syndrome (PMID: 32326958, 22033296, 30176936, 16155193). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site resulting in the insertion of five amino acid residues (PMID 29255276).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235096 SCV003933967 pathogenic Hypogonadotropic hypogonadism 5 with or without anosmia 2023-05-24 criteria provided, single submitter clinical testing Variant summary: CHD7 c.5405-17G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3 acceptor site. Multiple reports have shown experimental evidence that this variant affects mRNA splicing and activates the alternative 3 splice site (examples: Aref-Eshgh_2018 and Legendre_2018). The variant was absent in 246432 control chromosomes (gnomAD). c.5405-17G>A has been reported in the literature in multiple individuals affected with CHARGE syndrome (examples: Jongmans_2006, Janssen_2012, Aref-Eshgh_AJHG_2018, Wang_2020). Additionally, each of these publications have reported at-least one case as a de novo occurrence (examples: Jongmans_2006, Janssen_2012, Aref-Eshgh_AJHG_2018, Wang_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29255276, 29304373, 22461308, 16155193, 31965297). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000309868 SCV001958410 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000309868 SCV001966886 pathogenic not provided no assertion criteria provided clinical testing

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