Total submissions: 23
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV000258940 | SCV006581643 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2025-02-11 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279598 /PMID: 27031564 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Juno Genomics, |
RCV000258940 | SCV005417236 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | criteria provided, single submitter | clinical testing | Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology. | |
| Pittsburgh Clinical Genomics Laboratory, |
RCV000258940 | SCV005397762 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2024-05-03 | criteria provided, single submitter | clinical testing | This sequence variant is a single nucleotide substitution (C>T) at position 2188 of the coding sequence of the ADNP gene which changes the Arg730 codon to an early termination codon. Although this variant occurs in the last of 5 exons in this gene, it is predicted to generate a non-functional allele through the expression of a truncated protein (PMID: 29724491). This is a previously reported variant (ClinVar 279598) that has been observed de novo in individuals affected by autism spectrum disorder, intellectual disability, developmental disability, and Helsmoortel–Van der Aa syndrome (PMID: 38254177, 29724491, 38204290, 29475819, 35322241, 27031564, 35813072, 35920977, 38282129, 31029150, 35982159, 28675391, 28407407). This variant is absent from the gnomAD v4.0.0 population database (0/~1,461,000 alleles). Haploinsufficiency in ADNP is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PS2, PVS1 |
| Clinical Genetics Laboratory, |
RCV000497305 | SCV005199499 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics Lab, |
RCV000258940 | SCV004697720 | likely pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | criteria provided, single submitter | clinical testing | ||
| Illumina Laboratory Services, |
RCV000497305 | SCV003802802 | pathogenic | not provided | 2022-09-14 | criteria provided, single submitter | clinical testing | The ADNP c.2188C>T (p.Arg730Ter) nonsense variant results in the substitution of arginine at amino acid position 730 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. Across a selection of the available literature, the c.2188C>T variant, which is described as one of the most common pathogenic ADNP variants, has been reported in a heterozygous state in at least seven patients with ADNP-related neurodevelopmental disorder (PMID: 27031564; PMID: 28221363; PMID: 29475819; PMID: 29724491). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In-vitro cell culture studies showed that although the variant protein is able to translocate inside the nucleus and co-localize with its binding partner, it does so less efficiently in the pericentromeric heterochromatin region when compared to wild-type protein (PMID: 29911927). Based on the available evidence, the c.2188C>T (p.Arg730Ter) variant is classified as pathogenic for ADNP-related neurodevelopmental disorder. |
| Labcorp Genetics |
RCV000497305 | SCV003443957 | pathogenic | not provided | 2024-07-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg730*) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 373 amino acid(s) of the ADNP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 29911927). ClinVar contains an entry for this variant (Variation ID: 279598). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ADNP function (PMID: 29911927). This variant disrupts a region of the ADNP protein in which other variant(s) (p.Met1088Serfs*5) have been determined to be pathogenic (PMID: 28135719). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Institute of Medical Genetics and Applied Genomics, |
RCV000497305 | SCV001762078 | likely pathogenic | not provided | 2021-06-17 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000497305 | SCV001502397 | pathogenic | not provided | 2020-11-01 | criteria provided, single submitter | clinical testing | |
| Rady Children's Institute for Genomic Medicine, |
RCV000258940 | SCV001445901 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2019-05-14 | criteria provided, single submitter | clinical testing | This nonsense variant is found in exon 5 of 5 and is predicted to result in loss of normal protein function. This variant has been reported as Pathogenic by multiple clinical laboratories in the ClinVar database (Variation ID: 279598). Additionally, this variant has been previously reported in the literature as a de novo heterozygous change in patients with Helsmoortel-van der Aa Syndrome (PMID: 27031564, 29286531, 29724491). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.2188C>T (p.Arg730Ter) variant is classified as Pathogenic. |
| Institute of Human Genetics, |
RCV000258940 | SCV001428818 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2022-10-25 | criteria provided, single submitter | clinical testing | _x000D_This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP |
| Undiagnosed Diseases Network, |
RCV000258940 | SCV001245587 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2019-02-21 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV000258940 | SCV001190485 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2020-01-06 | criteria provided, single submitter | research | ACMG codes: PVS1, PS2, PS4M, PM2, PP5 |
| Fulgent Genetics, |
RCV000258940 | SCV000894222 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000623455 | SCV000742463 | pathogenic | Inborn genetic diseases | 2017-08-03 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000497305 | SCV000589497 | pathogenic | not provided | 2022-08-11 | criteria provided, single submitter | clinical testing | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 373 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29475819, 27031564, 29911927, 31029150, 29286531, 29724491, 31664177, 24531329, 28221363, 32661233, 33329371, 32758449, 31785789, 34930662, 33004838) |
| Center of Genomic medicine, |
RCV000258940 | SCV000537697 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2016-06-01 | criteria provided, single submitter | clinical testing | |
| MVZ Martinsried, |
RCV000258940 | SCV000328957 | pathogenic | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | 2016-09-30 | criteria provided, single submitter | clinical testing | |
| Genetics and Genomic Medicine Centre, |
RCV000497305 | SCV004175105 | pathogenic | not provided | 2021-10-10 | no assertion criteria provided | clinical testing | |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000497305 | SCV001974599 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000497305 | SCV001953192 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Gene |
RCV000258940 | SCV001832228 | not provided | ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder | no classification provided | literature only | Common pathogenic variant | |
| Centre for Mendelian Genomics, |
RCV000414762 | SCV000492629 | likely pathogenic | Corpus callosum, agenesis of; Global developmental delay; Seizure; Aggressive behavior; Hypothyroidism; Stereotypic movement disorder; Abnormality of the dentition; Decreased response to growth hormone stimulation test | 2016-03-21 | no assertion criteria provided | clinical testing |