NM_017780.4(CHD7):c.3082A>G (p.Ile1028Val) AND CHARGE syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 25, 2024
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:: RCV000002100.23

Allele description [Variation Report for NM_017780.4(CHD7):c.3082A>G (p.Ile1028Val)]

NM_017780.4(CHD7):c.3082A>G (p.Ile1028Val)

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.3082A>G (p.Ile1028Val)

HGVS:

NC_000008.11:g.60822627A>G
NG_007009.1:g.148848A>G
NM_001316690.1:c.1717-39602A>G
NM_017780.4:c.3082A>GMANE SELECT
NP_060250.2:p.Ile1028Val
NP_060250.2:p.Ile1028Val
NP_060250.2:p.Ile1028Val
LRG_176t1:c.3082A>G
LRG_176:g.148848A>G
LRG_176p1:p.Ile1028Val
NC_000008.10:g.61735186A>G
NM_017780.2:c.3082A>G
NM_017780.3:c.3082A>G
Q9P2D1:p.Ile1028Val

Protein change:

I1028V; ILE1028VAL

Links:

UniProtKB: Q9P2D1#VAR_021059; OMIM: 608892.0001; dbSNP: rs121434338

NCBI 1000 Genomes Browser:

rs121434338

Molecular consequence:

NM_001316690.1:c.1717-39602A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_017780.4:c.3082A>G - missense variant - [Sequence Ontology: SO:0001583]

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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Mus musculus synuclein, alpha (Snca), transcript variant 2, mRNA
Mus musculus synuclein, alpha (Snca), transcript variant 2, mRNA
gi|109638752|ref|NM_009221.2|

Nucleotide
Rpl23a ribosomal protein L23A [Mus musculus]
Rpl23a ribosomal protein L23A [Mus musculus]
Gene ID:268449

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022258	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000755739	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15300250, 16155193, 18073582, 20884005, 21158681, 22539353, 25472840, 28492532
SCV004171100	Laboratory of Medical Genetics, University of Torino	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005090978	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	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

Citations

PubMed

Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.

Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG.

Nat Genet. 2004 Sep;36(9):955-7. Epub 2004 Aug 8.

PubMed [citation]

PMID:: 15300250

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene.

Jongmans MC, Admiraal RJ, van der Donk KP, Vissers LE, Baas AF, Kapusta L, van Hagen JM, Donnai D, de Ravel TJ, Veltman JA, Geurts van Kessel A, De Vries BB, Brunner HG, Hoefsloot LH, van Ravenswaaij CM.

J Med Genet. 2006 Apr;43(4):306-14. Epub 2005 Sep 9.

PubMed [citation]

PMID:: 16155193
PMCID:: PMC2563221

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000022258.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a female patient with CHARGE syndrome (214800), Vissers et al. (2004) described a heterozygous 3082A-G transition in exon 12 of the CHD7 gene that resulted in an ile1028-to-val (I1028V) mutation. The patient had coloboma, retardation of growth and development, and semicircular canal agenesis. The mutation was de novo.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000755739.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2022). This missense change has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 18073582, 20884005, 21158681, 22539353). 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 replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1028 of the CHD7 protein (p.Ile1028Val). Experimental studies have shown that this missense change affects CHD7 function (PMID: 25472840). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.

#	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 Laboratory of Medical Genetics, University of Torino, SCV004171100.1

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

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

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005090978.1

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

Description

PS4, PS3, PM1, PM2, PP3- This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 2022).In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It is not present in population databases (gnomAD no frequency). It is reported previously as causative (PMID: 15300250, 16155193, 18073582, 20884005, 21158681, 22539353). Functional studies support pathogenic effect (PMID: 25472840).

#	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		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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