ClinVar Genomic variation as it relates to human health
NM_017780.4(CHD7):c.5405-7G>A
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017780.4(CHD7):c.5405-7G>A
Variation ID: 95795 Accession: VCV000095795.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q12.2 8: 60850486 (GRCh38) [ NCBI UCSC ] 8: 61763045 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 21, 2013 May 12, 2024 Jun 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017780.4:c.5405-7G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001316690.1:c.1717-11743G>A intron variant NC_000008.11:g.60850486G>A NC_000008.10:g.61763045G>A NG_007009.1:g.176707G>A LRG_176:g.176707G>A LRG_176t1:c.5405-7G>A - Protein change
- Other names
- IVS26AS, G-A, -7
- Canonical SPDI
- NC_000008.11:60850485:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- cryptic splice acceptor activation Variation Ontology [VariO:0375]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CHD7 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3239 | 3439 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2022 | RCV000081841.31 | |
Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000176678.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2018 | RCV001004923.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 16, 2016 | RCV001265704.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV003407463.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680169.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Pathogenic
(Jan 12, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000228369.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001480145.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Clinical Features:
Hypogonadotropic hypogonadism (present) , Hearing impairment (present) , Anosmia (present) , Strabismus (present) , Migraine (present) , Atrioventricular canal defect (present)
Sex: female
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518697.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Mar 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329268.9
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published in vitro splicing assay and RT-PCR studies indicate this variant creates a new splice acceptor site in intron 25 that results in abnormal gene … (more)
Published in vitro splicing assay and RT-PCR studies indicate this variant creates a new splice acceptor site in intron 25 that results in abnormal gene splicing resulting in a frameshift in the resultant product (Song et al., 2011; Legendre et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30216942, 30587507, 31130284, 21931733, 21158681, 16155193, 29255276, 22033296, 15300250, 32763379, 34008892, 32969205, 16615981) (less)
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Pathogenic
(Jul 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248377.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 05, 2017)
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criteria provided, single submitter
Method: in vitro
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CHARGE association
(Autosomal dominant inheritance)
Affected status: not applicable
Allele origin:
not applicable
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Laboratoire de Genetique Biologique, CHU de Poitiers
Accession: SCV000579496.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Comment:
found de novo on several CHARGE syndrome patients. Minigene assays confirm the use of a new acceptor splice site leading to frameshift in exon 26
Comment on evidence:
Minigene assays confirm the use of a new acceptor splice site
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Pathogenic
(Dec 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919211.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: CHD7 c.5405-7G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CHD7 c.5405-7G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts that the variant creates a cryptic 3 acceptor site. Two independent mini-gene assays confirm the impact on splicing, specificaly the introduction of a 5-bp intronic sequence by activation of a cryptic acceptor site leading to a frameshift mutation (Legendre_2018, Song_2011). The variant was absent in 275496 control chromosomes (gnomAD). The variant, c.5405-7G>A, has been reported in the literature in multiple individuals affected with CHARGE Syndrome (Vissers_2004, Bilan_2012, Janssen_2012, Song_2011, Legendre_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV000928399.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
Comment:
PS3, PM2, PM6, PP3, PP4, PP5
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Pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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Hypogonadotropic hypogonadism 5 with or without anosmia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164433.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous c.5405-7G>A variant in CHD7 was identified by our study in one individual with hypogonadotropic hypogonadism with or without anosmia. Trio exome analysis showed … (more)
The heterozygous c.5405-7G>A variant in CHD7 was identified by our study in one individual with hypogonadotropic hypogonadism with or without anosmia. Trio exome analysis showed this variant to be de novo and there are multiple reports of de novo inheritance in the literature (PMID: 15300250, 22033296). This variant was absent from large population studies and has been reported in ClinVar (Variation ID: 95795). In vitro functional studies provide some evidence that the c.5405-7G>A variant may impact protein function by causing a five base pair insertion during in vitro splicing (PMID: 21931733). However, these types of assays may not accurately represent biological function. In summary, the c.5405-7G>A variant is pathogenic based off of our findings and multiple de novo reports in the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PS3_Moderate (Richards 2015). (less)
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Pathogenic
(Dec 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506423.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
ACMG categories: PS2,PS3,PM2,PP3,PP4,PP5
Number of individuals with the variant: 1
Clinical Features:
Microphthalmia (present) , Syndactyly (present) , Esophageal atresia (present) , Abnormal facial shape (present) , Congenital ocular coloboma (present) , Abnormal cardiovascular system morphology (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572741.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21931733). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 15300250 , 22033296 ) and observed in multiple (>3) similarly affected unrelated individuals (PMID: 16155193 , 16615981 , 21158681 , 21931733). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000095795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal facial shape (present) , Short stature (present) , Decreased testicular size (present) , Micropenis (present) , Facial asymmetry (present)
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Pathogenic
(Sep 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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CHARGE syndrome
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000328342.2
First in ClinVar: Jun 28, 2015 Last updated: Mar 04, 2023
Comment:
Clinical Testing
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Number of individuals with the variant: 3
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Pathogenic
(Jun 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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CHD7-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116098.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CHD7 c.5405-7G>A variant is predicted to interfere with splicing. This is a well-documented recurrent pathogenic variant causative for CHARGE syndrome and has previously been … (more)
The CHD7 c.5405-7G>A variant is predicted to interfere with splicing. This is a well-documented recurrent pathogenic variant causative for CHARGE syndrome and has previously been reported as de novo (Bilan et al. 2012. PubMed ID: 22033296; Song et al. 2011. PubMed ID: 21931733). Functional studies found it creates a frameshift and premature protein termination by activating a cryptic splice acceptor site and introducing a five-base pair intronic sequence to the CHD7 messenger RNA (Song et al. 2011. PubMed ID: 21931733; Legendre et al. 2018. PubMed ID: 29255276). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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CHARGE association
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552237.10
First in ClinVar: Jun 28, 2015 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 95795). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this … (more)
ClinVar contains an entry for this variant (Variation ID: 95795). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21931733). This variant is also known as IVS25-7G>A and IVS26-7G>A. This variant has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 16615981, 21158681, 21931733, 22033296). 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 falls in intron 25 of the CHD7 gene. It does not directly change the encoded amino acid sequence of the CHD7 protein. (less)
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Pathogenic
(May 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001443871.3
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.5405-7G>A intronic pathogenic mutation results from a G to A substitution 7 nucleotides upstream from coding exon 25 in the CHD7 gene. This mutation … (more)
The c.5405-7G>A intronic pathogenic mutation results from a G to A substitution 7 nucleotides upstream from coding exon 25 in the CHD7 gene. This mutation has been reported in multiple individuals with a clinical diagnosis of CHARGE syndrome, including one de novo occurrence (Vissers LE, et al. Nat. Genet. 2004 Sep; 36(9):955-7; Jongmans MC, et al. J. Med. Genet. 2006 Apr; 43(4):306-14; Aramaki M, et al. J. Pediatr. 2006 Mar; 148(3):410-4; Song MH, et al. PLoS ONE. 2011; 6(9):e24511). In addition, an in vitro splicing analysis demonstrated the introduction of 5 additional nucleotides due to the activation of a cryptic acceptor site (Song MH, et al. PLoS ONE. 2011; 6(9):e24511). Based on the supporting evidence, c.5405-7G>A is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 01, 2004)
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no assertion criteria provided
Method: literature only
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CHARGE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022261.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2013 |
Comment on evidence:
In a male patient with CHARGE syndrome (214800), Vissers et al. (2004) found a de novo heterozygous splice site mutation, IVS26-7G-A, in the CHD7 gene. … (more)
In a male patient with CHARGE syndrome (214800), Vissers et al. (2004) found a de novo heterozygous splice site mutation, IVS26-7G-A, in the CHD7 gene. The patient had coloboma, heart malformation, retardation of growth and development, genital hypoplasia, ear abnormalities, and cleft lip/palate, but no choanal atresia. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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CHARGE association
Affected status: yes
Allele origin:
de novo
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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea
Accession: SCV004023321.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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cryptic splice acceptor activation
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Laboratoire de Genetique Biologique, CHU de Poitiers
Accession: SCV000579496.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays. | Legendre M | European journal of human genetics : EJHG | 2018 | PMID: 29255276 |
Mutation update on the CHD7 gene involved in CHARGE syndrome. | Janssen N | Human mutation | 2012 | PMID: 22461308 |
Complete screening of 50 patients with CHARGE syndrome for anomalies in the CHD7 gene using a denaturing high-performance liquid chromatography-based protocol: new guidelines and a proposal for routine diagnosis. | Bilan F | The Journal of molecular diagnostics : JMD | 2012 | PMID: 22033296 |
CHD7 mutational analysis and clinical considerations for auditory rehabilitation in deaf patients with CHARGE syndrome. | Song MH | PloS one | 2011 | PMID: 21931733 |
Mutations in the CHD7 gene: the experience of a commercial laboratory. | Bartels CF | Genetic testing and molecular biomarkers | 2010 | PMID: 21158681 |
Phenotypic spectrum of CHARGE syndrome with CHD7 mutations. | Aramaki M | The Journal of pediatrics | 2006 | PMID: 16615981 |
CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. | Jongmans MC | Journal of medical genetics | 2006 | PMID: 16155193 |
Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. | Vissers LE | Nature genetics | 2004 | PMID: 15300250 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CHD7 | - | - | - | - |
Text-mined citations for rs398124321 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.