NM_017780.4(CHD7):c.7198C>T (p.Arg2400Trp) AND CHARGE syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 10, 2021
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:: RCV001973704.6

Allele description

NM_017780.4(CHD7):c.7198C>T (p.Arg2400Trp)

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.7198C>T (p.Arg2400Trp)

HGVS:

NC_000008.11:g.60856478C>T
NG_007009.1:g.182699C>T
NM_001316690.1:c.1717-5751C>T
NM_017780.4:c.7198C>TMANE SELECT
NP_060250.2:p.Arg2400Trp
LRG_176:g.182699C>T
NC_000008.10:g.61769037C>T

Protein change:

R2400W

Links:

dbSNP: rs770959300

NCBI 1000 Genomes Browser:

rs770959300

Molecular consequence:

NM_001316690.1:c.1717-5751C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_017780.4:c.7198C>T - 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

Recent activity

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zinc finger and SCAN domain-containing protein 30 isoform 1 [Homo sapiens]
zinc finger and SCAN domain-containing protein 30 isoform 1 [Homo sapiens]
gi|260436846|ref|NP_001159484.1|

Protein
RecName: Full=Zinc finger and SCAN domain-containing protein 30; AltName: Full=Z...
RecName: Full=Zinc finger and SCAN domain-containing protein 30; AltName: Full=ZNF-WYM; AltName: Full=Zinc finger protein 397 opposite strand; AltName: Full=Zinc finger protein 397OS
gi|74759452|sp|Q86W11.1|ZSC30_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002259770	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005042885	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	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

SCV002259770

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 10, 2021)

germline

clinical testing

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

SCV005042885

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV002259770.3

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHD7 protein function. This variant has not been reported in the literature in individuals with CHD7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with tryptophan at codon 2400 of the CHD7 protein (p.Arg2400Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005042885.1

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

Description

The missense c.7198C>T p.Arg2400Trp variant in CHD7 gene has been previously reported in an individual affected with CHD-7 related disorders Neocleous et al., 2020. The p.Arg2400Trp variant has been reported with allele frequency of 0.001% in gnomAD exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Arg2400Trp in CHD7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 2400 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.

#	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: Jun 2, 2024

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