NM_017780.4:c.6955C>T

Variant names:

• chr8-60855993-C-T
• rs121434341
• NM_017780.4:c.6955C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_017780.4(CHD7):​c.6955C>T​(p.Arg2319Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2319H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.85
• Publications: 14 publications found

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

CHD7 Gene-Disease associations (from GenCC):

• CHARGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• hypogonadotropic hypogonadism 5 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-60855994-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1186535.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 8-60855993-C-T is Pathogenic according to our data. Variant chr8-60855993-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 235889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.6955C>T	p.Arg2319Cys	missense_variant	Exon 33 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.6955C>T	p.Arg2319Cys	missense_variant	Exon 33 of 38	5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:6

Jun 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2319 of the CHD7 protein (p.Arg2319Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CHARGE syndrome (PMID: 16155193, 16763960, 18073582, 18484313, 21158681, 22033296, 28554332; Feretetal.ACMG2010Abstract#1671). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 235889). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CHD7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg2319 amino acid residue in CHD7. Other variant(s) that disrupt this residue have been observed in individuals with CHD7-related conditions (PMID: 16400610), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Laboratoire de Genetique Biologique, CHU de Poitiers

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.6955C>T (p.Arg2319Cys)) in the CHD7 gene has been reported previously in heterozygous state in individuals affected with CHARGE syndrome (Brajadenta et al., 2019; Holak et al., 2008). Different amino acid change (p.Arg2319His) is reported as a known likely pathogenic variant. In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. -

Aug 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome Pathogenic:1

Jun 06, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHD7-related disorder Pathogenic:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHD7 c.6955C>T variant is predicted to result in the amino acid substitution p.Arg2319Cys. This variant has been reported in individuals with CHARGE syndrome of variable severity (Table S1, Bergman et al. 2012. PubMed ID: 22539353; Table S1, Bowling et al. 2017. PubMed ID: 28554332; Table S2, Cheng et al. 2019. PubMed ID: 31729160; Table 1, Dosunmu and Castleberry. 2020. PubMed ID: 32914532; Holak et al. 2008. PubMed ID: 18484313; Table 2, Jongmans et al. 2006. PubMed ID: 16155193; Lee et al. 2020. PubMed ID: 33442180; Brajadenta et al. 2019. PubMed ID: 31289371; Wei et al. 2020. PubMed ID: 32978145). This variant has been confirmed de novo in five of these unrelated individuals (Table S1, Bowling et al. 2017. PubMed ID: 28554332; Brajadenta et al. 2019. PubMed ID: 31289371; Table S2, Cheng et al. 2019. PubMed ID: 31729160; Lee et al. 2020. PubMed ID: 33442180; Table 2, Wei et al. 2020. PubMed ID: 32804436). In one family this variant was observed in the mildly affected mother of the proband (Table 1, Figure 4, Lalani et al. 2006. PubMed ID: 16400610). In vitro experimental studies suggest this variant impacts protein function (Figure 4, Brajadenta et al. 2019. PubMed ID: 31289371). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Jan 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest this variant alters gene transcription (PMID: 31289371); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22539353, 21158681, 31729160, 16155193, 18484313, 16763960, 18073582, 31289371, 32914532, 22033296, 33442180, 32978145, 32804436, 34716235, 28554332, 36597107) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Gain of catalytic residue at L2320 (P = 0.0195);
MVP		0.99
MPC		0.67
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.78
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434341; hg19: chr8-61768552;