ClinVar Genomic variation as it relates to human health
NM_017780.4(CHD7):c.3973T>C (p.Tyr1325His)
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.
Uncertain significance(3); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017780.4(CHD7):c.3973T>C (p.Tyr1325His)
Variation ID: 194665 Accession: VCV000194665.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q12.2 8: 60836267 (GRCh38) [ NCBI UCSC ] 8: 61748826 (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 Dec 26, 2017 May 12, 2024 Feb 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017780.4:c.3973T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060250.2:p.Tyr1325His missense NM_001316690.1:c.1717-25962T>C intron variant NC_000008.11:g.60836267T>C NC_000008.10:g.61748826T>C NG_007009.1:g.162488T>C LRG_176:g.162488T>C LRG_176t1:c.3973T>C - Protein change
- Y1325H
- Other names
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- Canonical SPDI
- NC_000008.11:60836266:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00017
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
3241 | 3441 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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May 1, 2023 | RCV000175090.18 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000531900.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001162409.4 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 27, 2021 | RCV002516660.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 7, 2024 | RCV003422067.5 |
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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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Kallmann Syndrome 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001324360.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Nov 27, 2020)
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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: SCV001825759.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Reported in an individual with normosmic congenital hypogonadotropic hypogonadism and an individual with atrial ventricular septal defects (D'Alessandro et al., 2016; Cassatella et al., 2018); … (more)
Reported in an individual with normosmic congenital hypogonadotropic hypogonadism and an individual with atrial ventricular septal defects (D'Alessandro et al., 2016; Cassatella et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32724172, 31200363, 25996639, 29419413) (less)
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Likely benign
(Jan 25, 2024)
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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: SCV000631249.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(Oct 27, 2021)
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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: SCV003644063.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(May 01, 2023)
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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: SCV004155856.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
CHD7: PP3, BS2
Number of individuals with the variant: 1
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Uncertain significance
(Jul 26, 2018)
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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: SCV000226518.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Uncertain significance
(Feb 07, 2024)
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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: SCV004117245.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The CHD7 c.3973T>C variant is predicted to result in the amino acid substitution p.Tyr1325His. This variant has been previously reported in an individual with atrioventricular … (more)
The CHD7 c.3973T>C variant is predicted to result in the amino acid substitution p.Tyr1325His. This variant has been previously reported in an individual with atrioventricular septum defect (D'Alessandro et al. 2016. PubMed ID: 25996639), and an individual with congenital hypogonadotropic hypogonadism (Table S2, Cassatella et al. 2018. PubMed ID: 29419413). An alternate nucleotide change affecting the same amino acid (c.3973T>G; p.Tyr1325Asp) has been observed in a cohort of individuals with CHARGE syndrome (Bergman et al. 2011. PubMed ID: 20884005), and reported as de novo (Table S1, Bergman et al. 2012. PubMed ID: 22539353). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553490.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHD7 p.Tyr1325His variant was identified in 1 of 162 proband chromosomes (frequency: 0.0062) from individuals with atrioventricular septal defect (AVSD) (D'Alessandro_2016_PMID:25996639). The variant was … (more)
The CHD7 p.Tyr1325His variant was identified in 1 of 162 proband chromosomes (frequency: 0.0062) from individuals with atrioventricular septal defect (AVSD) (D'Alessandro_2016_PMID:25996639). The variant was also identified in dbSNP (ID: rs377535841), ClinVar (classified as a VUS by EGL Genetics and Invitae) and LOVD 3.0. The variant was also identified in control databases in 19 of 279988 chromosomes at a frequency of 0.000068 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7114 chromosomes (freq: 0.000141), European (non-Finnish) in 17 of 128040 chromosomes (freq: 0.000133) and Latino in 1 of 35274 chromosomes (freq: 0.000028), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Tyr1325 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951342.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972125.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CHD7 | - | - | - | - |
Text-mined citations for rs377535841 ...
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.