Submissions for variant NM_001005273.3(CHD3):c.5007_5008del (p.Asp1671fs)

gnomAD frequency: 0.00001  dbSNP: rs967826828

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002274476	SCV002559215	likely pathogenic	Snijders Blok-Campeau syndrome		criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002274476	SCV002583673	likely pathogenic	Snijders Blok-Campeau syndrome	2022-09-02	criteria provided, single submitter	clinical testing	PVS1, PM2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002274476	SCV002767002	likely pathogenic	Snijders Blok-Campeau syndrome	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Snijders Blok-Campeau syndrome (MIM#618205), however no clear genotype-phenotype correlations have been identified to determine how both overactivity and underactivity of CHD3 can result in the same phenotype (PMID: 32483341). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity with inheritance from mildly affected or unaffected parents reported (PMID 35346573). (I) 0202 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction), but is located in an exon that may undergo alternative splicing. (SP) 0219 - This variant is non-coding in an alternative transcript (NM_005852.3). The functional relevance of this transcript has not been established. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, LOVD, PMID 30397230; PMID 35346573). However, there have been no previously reported pathogenic NMD-predicted variants in exon 33 which may be subject to alternative splicing. (SP) 0808 - Previous evidence of pathogenicity for this variant is conflicting. This variant has been previously reported as a variant of uncertain significance (DECIPHER). It was heterozygous in an individual with global developmental delay and inherited from a mother with speech delay. This individual also had a pathogenic heterozygous de novo variant in the SETD5 gene. In addition, this variant has been recently reported as likely pathogenic in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002274476	SCV002822964	pathogenic	Snijders Blok-Campeau syndrome	2019-08-13	criteria provided, single submitter	clinical testing	The c.5007_5008del variant in the CHD3 gene is predicted to cause a frameshift at p.Asp1671 that would likely result in nonsense mediated RNA decay (NMD). This variant localizes to coding exon 33/40 of the CHD3 gene (NM_001005273.3), where loss of function is a known mechanism of the disease (PMID: 30397230). This variant is present in the Genome Aggregation Database (gnomAD) at a very low frequency (1/31,334), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this specific variant has not been reported in the literature, ClinVar and HGMD databases. However, several truncating variants have been described as disease-causing, including one frameshift variant resulting in premature stop codon closer to the C-terminus (PMID: 30397230). As a rare, truncating change seen in a gene that is constrained for truncating variants, the c.5007_5008del, p.Asp1671PhefsTer10 variant in CHD3 is classified as Pathogenic.
Ambry Genetics	RCV003096171	SCV003592833	uncertain significance	Inborn genetic diseases	2022-06-13	criteria provided, single submitter	clinical testing	Loss of function has not been established as a mechanism of disease Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV002274476	SCV005016518	likely pathogenic	Snijders Blok-Campeau syndrome	2024-04-11	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002274476	SCV005091089	likely pathogenic	Snijders Blok-Campeau syndrome	2024-03-14	criteria provided, single submitter	clinical testing	PVS1, PM2 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 1700227).
CeGaT Center for Human Genetics Tuebingen	RCV004729130	SCV005330633	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CHD3: PVS1, PM2:Supporting, PM6:Supporting, PS4:Supporting
PreventionGenetics, part of Exact Sciences	RCV003943339	SCV004761583	likely pathogenic	CHD3-related disorder	2024-03-18	no assertion criteria provided	clinical testing	The CHD3 c.5184_5185delAG variant is predicted to result in a frameshift and premature protein termination (p.Asp1730Phefs*10). This variant has been reported as de novo in a patient with Snijders Blok–Campeau syndrome (Pascual et al. 2023. PubMed ID: 37761804). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CHD3 are expected to be pathogenic. This variant is interpreted as likely pathogenic.