rs587783457

Positions:

• chr8-60862256-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.7891C>T​(p.Arg2631Ter) 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: 33)
• Consequence: CHD7 NM_017780.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.90

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 8-60862256-C-T is Pathogenic according to our data. Variant chr8-60862256-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.7891C>T	p.Arg2631Ter	stop_gained	36/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.7891C>T	p.Arg2631Ter	stop_gained	36/38	5	NM_017780.4	ENSP00000392028	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2019	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). This variant has been observed in individual(s) with clinical features of CHARGE syndrome (PMID: 26666243, 21158681). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg2631*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The inframe deletion c.1521_1523del (p.Phe508del) variant in the CFTR gene has been reported previously in multiple individuals in homozygous/ compound heterozygous state affected with Cystic fibrosis (Sosnay et al., 2013; Terlizzi et al., 2021). The p.Phe508del variant is the most frequent deletion that occurs in ~85% of Cystic fibrosis patients worldwide and is described to affect CFTR (class II) protein processing (Awatade et al. 2019). Experimental studies have shown that this variant affects CFTR function (Zeiher et al. 1995). The p.Phe508del variant is reported with an allele frequency of 0.7% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This p.Phe508del causes the deletion of the amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2015	The R2631X nonsense variant in the CHD7 gene has been reported previously in association with CHARGE syndrome (Bartels et al. 2010). Approximately 45% of CHD7 pathogenic variants are nonsense changes predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay (Janssen et al., 2012; Zentner et al, 2010). Therefore, we consider R2631X to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 24, 2019	The CHD7 c.7891C>T; p.Arg2631Ter variant (rs587783457) is reported in the medical literature in several individuals with CHARGE syndrome (Bartels 2010). The variant is reported in the ClinVar database (Variation ID: 158320) and is absent from general population databases (Exome Variant Server, 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. Considering available information, this variant is classified as 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. -

CHD7-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2024

The CHD7 c.7891C>T variant is predicted to result in premature protein termination (p.Arg2631*). This variant has been reported in multiple individuals with CHARGE syndrome (Bartels et al. 2010. PubMed ID: 21158681; Wei et al. 2020. PubMed ID: 32804436). 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. -

Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 16, 2024

Variant summary: CHD7 c.7891C>T (p.Arg2631X) 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. The variant was absent in 244614 control chromosomes. c.7891C>T has been reported in the literature as heterozygous genotype in multiple individuals affected with clinical features of CHARGE syndrome (Bartels_2010, Lim_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21158681, 26666243). ClinVar contains an entry for this variant (Variation ID: 158320). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.79
GERP RS		5.6

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: rs587783457; hg19: chr8-61774815; COSMIC: COSV71113106; COSMIC: COSV71113106;