NM_017780.4(CHD7):c.1735C>T (p.Gln579Ter) AND CHARGE syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 27, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000542683.13

Allele description [Variation Report for NM_017780.4(CHD7):c.1735C>T (p.Gln579Ter)]

NM_017780.4(CHD7):c.1735C>T (p.Gln579Ter)

Genes:

LOC126860403:CDK7 strongly-dependent group 2 enhancer GRCh37_chr8:61693034-61694233 [Gene]
CHD7:chromodomain helicase DNA binding protein 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q12.2

Genomic location:

Preferred name:

NM_017780.4(CHD7):c.1735C>T (p.Gln579Ter)

HGVS:

NC_000008.11:g.60781069C>T
NG_007009.1:g.107290C>T
NM_001316690.1:c.1716+19C>T
NM_017780.4:c.1735C>TMANE SELECT
NP_060250.2:p.Gln579Ter
LRG_176:g.107290C>T
NC_000008.10:g.61693628C>T
NM_017780.3:c.1735C>T

Protein change:

Q579*

Links:

dbSNP: rs780953224

NCBI 1000 Genomes Browser:

rs780953224

Molecular consequence:

NM_001316690.1:c.1716+19C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_017780.4:c.1735C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: CHARGE syndrome (CHARGE)
Synonyms:: CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES; Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies; CHARGE association; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008965; MedGen: C0265354; Orphanet: 138; OMIM: 214800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000631241	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 18, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22461308, 28492532
SCV002764971	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jun 27, 2019)	de novo	clinical testing	Citation Link,
SCV003845202	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000631241

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 18, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002764971

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Pathogenic
(Jun 27, 2019)

de novo

clinical testing

Citation Link,

SCV003845202

Lifecell International Pvt. Ltd

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation update on the CHD7 gene involved in CHARGE syndrome.

Janssen N, Bergman JE, Swertz MA, Tranebjaerg L, Lodahl M, Schoots J, Hofstra RM, van Ravenswaaij-Arts CM, Hoefsloot LH.

Hum Mutat. 2012 Aug;33(8):1149-60. doi: 10.1002/humu.22086. Epub 2012 Apr 16. Review.

PubMed [citation]

PMID:: 22461308

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000631241.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CHD7 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with CHARGE syndrome (PMID: 22461308). This sequence change creates a premature translational stop signal at codon 579 (p.Gln579*) of the CHD7 gene. It is expected to result in an absent or disrupted protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764971.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003845202.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (1)

Description

A Heterozygous Nonsense variant c.1735C>T in Exon 3 of the CHD7 gene that results in the amino acid substitution p.Gln579* was identified. The observed variant novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 459542). For this reasons, this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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