rs587783455

Positions:

• chr8-60856532-C-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.7252C>T​(p.Arg2418*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 33)
• Consequence: CHD7 NM_017780.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.66

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 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 8-60856532-C-T is Pathogenic according to our data. Variant chr8-60856532-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60856532-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.7252C>T	p.Arg2418*	stop_gained	34/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.7252C>T	p.Arg2418*	stop_gained	34/38	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2022	This premature translational stop signal has been observed in individual(s) with CHARGE syndrome (PMID: 16155193, 21158681, 21554267, 22462537). In at least one individual the variant was observed to be de novo. 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. ClinVar contains an entry for this variant (Variation ID: 158314). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2418*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported as pathogenic more than twice with clinical assertions and evidence for the classification (ClinVar ID: VCV000158314). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2022	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 (gnomAD); This variant is associated with the following publications: (PMID: 26928066, 21554267, 22462537, 21158681, 16155193, 32410215, 25525159) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jun 26, 2019	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 09, 2018

The CHD7 c.7252C>T p.Arg2418Ter variant (rs587783455) is reported in the literature in multiple individuals affected with CHARGE syndrome (Bartels 2010, Husu 2013, Jongmans 2006, Pauli 2012). In one affected individual, parental testing for the variant suggested a de novo origin (Bartels 2010). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 158314). It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bartels CF et al. Mutations in the CHD7 gene: the experience of a commercial laboratory. Genet Test Mol Biomarkers. 2010 Dec;14(6):881-91. Husu E et al. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome. Clin Genet. 2013 Feb;83(2):125-34. Jongmans MC et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006 Apr;43(4):306-14 Pauli S et al. CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin Genet. 2012 Mar;81(3):234-9. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.95
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs587783455; hg19: chr8-61769091;