NM_017780.4:c.2839C>T

Variant names:

• chr8-60822027-C-T
• rs200220845
• NM_017780.4:c.2839C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017780.4(CHD7):​c.2839C>T​(p.Arg947*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-60822027-C-T is Pathogenic according to our data. Variant chr8-60822027-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 95781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60822027-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.2839C>T	p.Arg947*	stop_gained	Exon 11 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.2839C>T	p.Arg947*	stop_gained	Exon 11 of 38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-40202C>T		intron_variant	Intron 2 of 4	1		ENSP00000437061.1
CHD7	ENST00000525508.1	c.2839C>T	p.Arg947*	stop_gained	Exon 10 of 12	5		ENSP00000436027.1
CHD7	ENST00000695853.1	n.2839C>T		non_coding_transcript_exon_variant	Exon 11 of 37			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 20, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16615981, 25525159, 32804436, 32978145, 30287924, 24979395, 28475860, 18445044) -

Oct 18, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHARGE syndrome Pathogenic:2

Feb 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHD7 c.2839C>T (p.Arg947X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248812 control chromosomes (gnomAD). c.2839C>T has been reported in the literature in multiple individuals affected with CHARGE Syndrome, including several cases where it has been confirmed to be a de novo occurrence (e.g. Aramaki_2006, Wincent_2008, Janssen_2012, Green_2014, Hale_2016, Wei_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 95781). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with CHARGE syndrome (PMID: 16615981, 33142350). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg947*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). -

CHD7-related disorder Pathogenic:1

Mar 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHD7 c.2839C>T variant is predicted to result in premature protein termination (p.Arg947*). This variant has been previously reported in individuals with CHARGE syndrome (see for example Aramaki et al. 2006. PubMed ID: 16615981; Butcher et al. 2017. PubMed ID: 28475860, Table S5; Wei et al. 2020. PubMed ID: 32978145, Supplementary Table 2), or cardiac related abnormalities (Van der Sluijs et al. 2018. PubMed ID: 30287924; Table S1). It has been documented as de novo in several patients (Wei et al. 2020. PubMed ID: 32804436; Zhu et al. 2022. PubMed ID: 35726512). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHD7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.85
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs200220845; hg19: chr8-61734586; COSMIC: COSV71107204;