8-60855993-C-T

Position:

• chr8-60855993-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.85

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD7. . Gene score misZ 3.2193 (greater than the threshold 3.09). Trascript score misZ 3.9401 (greater than threshold 3.09). GenCC has associacion of gene with Kallmann syndrome, hypogonadotropic hypogonadism 5 with or without anosmia, CHARGE syndrome, hypogonadotropic hypogonadism, Omenn syndrome.
• 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 id is 235889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60855993-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.6955C>T	p.Arg2319Cys	missense_variant	33/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.6955C>T	p.Arg2319Cys	missense_variant	33/38	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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 30, 2023	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). 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 expected to disrupt CHD7 protein function. 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. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Genetique Biologique, CHU de Poitiers	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Jun 29, 2024	- -

CHD7-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 02, 2024

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
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

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: rs121434341; hg19: chr8-61768552;