VCV000279598.47 - ClinVar

NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter)

Variation ID: 279598 Accession: VCV000279598.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.13 20: 50892526 (GRCh38) [ NCBI UCSC ] 20: 49509063 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 25, 2016	Nov 17, 2024	May 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001282531.3:c.2188C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001269460.1:p.Arg730Ter	nonsense
NM_001282532.2:c.2188C>T	NP_001269461.1:p.Arg730Ter	nonsense
NM_001347511.2:c.2188C>T	NP_001334440.1:p.Arg730Ter	nonsense
NM_015339.5:c.2188C>T	NP_056154.1:p.Arg730Ter	nonsense
NM_181442.4:c.2188C>T	NP_852107.1:p.Arg730Ter	nonsense
NC_000020.11:g.50892526G>A
NC_000020.10:g.49509063G>A
NG_034200.1:g.43465C>T

... more HGVS ... less HGVS

Protein change

R730*

Other names

Canonical SPDI

NC_000020.11:50892525:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10602716 dbSNP: rs886041116 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ADNP		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	700	717

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	May 3, 2024	RCV000258940.14
not provided	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Sep 1, 2023	RCV000497305.34
Abnormality of the dentition Aggressive behavior Corpus callosum, agenesis of Decreased response to growth hormone stimulation test Global developmental delay Hypothyroidism Seizure Stereotypic movement disorder	Likely pathogenic (1)	no assertion criteria provided	Mar 21, 2016	RCV000414762.3
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Aug 3, 2017	RCV000623455.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 30, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: yes Allele origin: de novo	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues Accession: SCV000328957.1 First in ClinVar: Nov 25, 2016 Last updated: Nov 25, 2016
Pathogenic (Jun 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000537697.1 First in ClinVar: Nov 25, 2016 Last updated: Nov 25, 2016	Age: 5-10 years Sex: male
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894222.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jan 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: yes Allele origin: de novo	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV001190485.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Comment: ACMG codes: PVS1, PS2, PS4M, PM2, PP5 Number of individuals with the variant: 1 Clinical Features: Cleft palate (present) , Low-set, posteriorly rotated ears (present) , Cryptorchidism (present) , Hypertonia (present) , Exaggerated startle response (present) , Apnea (present) , Cleft … (more) Cleft palate (present) , Low-set, posteriorly rotated ears (present) , Cryptorchidism (present) , Hypertonia (present) , Exaggerated startle response (present) , Apnea (present) , Cleft palate (present) , Unilateral cryptorchidism (present) , Hypoplasia of the corpus callosum (present) , Ventriculomegaly (present) , Bilateral single transverse palmar creases (present) , Sacral dimple (present) (less)
Pathogenic (Feb 21, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Accession: SCV001245587.1 First in ClinVar: May 12, 2020 Last updated: May 12, 2020	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 Number of individuals with the variant: 1 Clinical Features: Widened cerebral subarachnoid space (present) , Ventriculomegaly (present) , Thick corpus callosum (present) , Sound sensitivity (present) , Small hand (present) , Small basal ganglia … (more) Widened cerebral subarachnoid space (present) , Ventriculomegaly (present) , Thick corpus callosum (present) , Sound sensitivity (present) , Small hand (present) , Small basal ganglia (present) , Single transverse palmar crease (present) , Short stature (present) , Short palm (present) , Short neck (present) , Short foot (present) , Short attention span (present) , Severe temper tantrums (present) , Severe short stature (present) , Severe receptive language delay (present) , Severe expressive language delay (present) , Secondary Caesarian section (present) , Scoliosis (present) , Reduced brain N-acetyl aspartate level by MRS (present) , Receptive language delay (present) , Proportionate short stature (present) , Postnatal microcephaly (present) , Plagiocephaly (present) , Mood changes (present) , Mongolian blue spot (present) , Microcephaly (present) , Low femoral bone density (present) , Irritability (present) , Intellectual disability, moderate (present) , Inflexible adherence to routines or rituals (present) , Impaired social interactions (present) , Hypoplasia of the corpus callosum (present) , Hypoplasia of the brainstem (present) , Hyperplasia of midface (present) , Hyperpigmentation of the skin (present) , High, narrow palate (present) , Global developmental delay (present) , Frequent temper tantrums (present) , Expressive language delay (present) , Enlarged sylvian cistern (present) , Dislocated radial head (present) , Depressed nasal bridge (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Decreased body weight (present) , Coxa valga (present) , Corpus callosum atrophy (present) , Conductive hearing impairment (present) , Coarse facial features (present) , Cerebral cortical atrophy (present) , Caesarian section (present) , Bridged palmar crease (present) , Brachycephaly (present) , Bilateral conductive hearing impairment (present) , Behavioral abnormality (present) , Atrophy/Degeneration affecting the brainstem (present) , Abnormality of the upper limb (present) , Abnormality of the cerebral ventricles (present) , Abnormality of the cerebral cortex (present) , Abnormality of the basal ganglia (present) , Abnormality of brainstem morphology (present) , Abnormal temper tantrums (present) , Abnormality of the subarachnoid space (present) , Abnormal social behavior (present) , Abnormal facial shape (present) , Abnormal emotion/affect behavior (present) , Abnormal delivery (present) , Abnormality of the corpus callosum (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Asian Tissue: blood Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2019-02-21 Testing laboratory interpretation: Pathogenic
Pathogenic (May 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HELSMOORTEL-VAN DER AA SYNDROME Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001445901.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: 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 … (more) 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. (less)
Likely pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762078.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Intellectual disability (present) , Autism (present) , Seizure (present) Sex: female
Pathogenic (Oct 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428818.2 First in ClinVar: Aug 15, 2020 Last updated: Oct 29, 2022	Comment: _x000D_This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP
Pathogenic (Aug 03, 2017)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742463.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (6) PubMed: 28221363‚ 24531329‚ 29911927‚ 29724491‚ 27031564‚ 29475819 Observation 1: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Hispanic Observation 2: Number of individuals with the variant: 1 Clinical Features: Congenital cerebellar hypoplasia (present) , Cerebral white matter hypoplasia (present) , Talipes cavus equinovarus (present) , Generalized limb muscle atrophy (present) , Aggressive behavior (present) … (more) Congenital cerebellar hypoplasia (present) , Cerebral white matter hypoplasia (present) , Talipes cavus equinovarus (present) , Generalized limb muscle atrophy (present) , Aggressive behavior (present) , Self-injurious behavior (present) , Global developmental delay (present) , Intellectual disability (present) , Short stature (present) , Failure to thrive (present) , Insomnia (present) , Constipation (present) , Vitamin D deficiency (present) , Abnormal serum iron (present) , Generalized hypotonia (present) , Long face (present) , Flat occiput (present) , Hypertelorism (present) , Deeply set eye (present) , Long nose (present) , Abnormality of the nasal bridge (present) , Broad nasal tip (present) , Hypoplastic fingernail (present) (less) Sex: male Ethnicity/Population group: Asian
Pathogenic (Sep 14, 2022)	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020) Method: clinical testing	Not provided Affected status: yes Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV003802802.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (5) PubMed: 29724491‚ 29475819‚ 27031564‚ 28221363‚ 29911927 Comment: 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 … (more) 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. (less)
Pathogenic (Aug 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589497.4 First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Sep 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003443957.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28135719‚ 29911927 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ADNP protein in which other variant(s) (p.Met1088Serfs5) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ADNP protein in which other variant(s) (p.Met1088Serfs5) 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. Experimental studies have shown that this premature translational stop signal affects ADNP function (PMID: 29911927). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 279598). This premature translational stop signal has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 29911927). This variant is not present in population databases (gnomAD no frequency). 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. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: yes Allele origin: de novo	Molecular Genetics Lab, CHRU Brest Accession: SCV004697720.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199499.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001502397.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (May 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397762.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (13) PubMed: 35920977‚ 38282129‚ 28407407‚ 38254177‚ 38204290‚ 29724491‚ 35322241‚ 31029150‚ 28675391‚ 27031564‚ 29475819‚ 35982159‚ 35813072 Comment: 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 … (more) 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 (less)
Likely pathogenic (Mar 21, 2016)	no assertion criteria provided Method: clinical testing	Abnormality of the dentition Corpus callosum, agenesis of Aggressive behavior Global developmental delay Decreased response to growth hormone stimulation test Hypothyroidism Seizure Motor stereotypies Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492629.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953192.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974599.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Oct 10, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare Accession: SCV004175105.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Clinical Features: delayed speech and language development (present) , intellectual disability (present) , behavioral abnormality (present) , Microcephaly (present) , hypotonia (present) , abnormal facial shape (present) Age: 0-9 years Sex: female Ethnicity/Population group: South East Asian Geographic origin: Bangladesh
not provided (-)	no classification provided Method: literature only	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001832228.2 First in ClinVar: Sep 08, 2021 Last updated: Oct 01, 2022	Publications: BookShelf: NBK355518 BookShelf: NBK355518 Comment: Common pathogenic variant
click to load more click to collapse

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this premature translational stop signal affects ADNP function (PMID: 29911927). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 279598). This premature translational stop signal has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 29911927). This variant is not present in population databases (gnomAD no frequency). 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.

Comment:

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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males.	Levine J	Journal of molecular neuroscience : MN	2024	PMID: 38282129
Clinical impact and in vitro characterization of ADNP variants in pediatric patients.	Ge C	Molecular autism	2024	PMID: 38254177
Extended phenotypic characterization of a novel Helsmoortel-van der Aa syndrome case series.	Pascolini G	American journal of medical genetics. Part A	2024	PMID: 38204290
Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.	Zhou X	Nature genetics	2022	PMID: 35982159
Vineland Adaptive Behavior Scale in a Cohort of Four ADNP Syndrome Patients Implicates Age-Dependent Developmental Delays with Increased Impact of Activities of Daily Living.	Levine J	Journal of molecular neuroscience : MN	2022	PMID: 35920977
Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders.	Krgovic D	Frontiers in molecular neuroscience	2022	PMID: 35813072
Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability.	Brea-Fernández AJ	European journal of human genetics : EJHG	2022	PMID: 35322241
ADNP-Related Disorder.	Adam MP	-	2022	PMID: 27054228
Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome.	Bend EG	Clinical epigenetics	2019	PMID: 31029150
Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.	Van Dijck A	Biological psychiatry	2019	PMID: 29724491
Mutations in ADNP affect expression and subcellular localization of the protein.	Cappuyns E	Cell cycle (Georgetown, Tex.)	2018	PMID: 29911927
Helsmoortel-Van der Aa Syndrome as emerging clinical diagnosis in intellectually disabled children with autistic traits and ocular involvement.	Pascolini G	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2018	PMID: 29475819
Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children.	Gozes I	Translational psychiatry	2017	PMID: 28675391
Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene.	Takenouchi T	American journal of medical genetics. Part A	2017	PMID: 28407407
Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children.	Gozes I	Translational psychiatry	2017	PMID: 28221363
Prevalence and architecture of de novo mutations in developmental disorders.	Deciphering Developmental Disorders Study	Nature	2017	PMID: 28135719
Additional data on the clinical phenotype of Helsmoortel-Van der Aa syndrome associated with a novel truncating mutation in ADNP gene.	Krajewska-Walasek M	American journal of medical genetics. Part A	2016	PMID: 27031564
A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP.	Helsmoortel C	Nature genetics	2014	PMID: 24531329
click to load more click to collapse

Text-mined citations for rs886041116 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041116 ...