NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter) AND ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder - ClinVar

NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter) AND ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: May 3, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000258940.14

Allele description [Variation Report for NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter)]

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

Gene:

ADNP:activity dependent neuroprotector homeobox [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.13

Genomic location:

Preferred name:

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

HGVS:

NC_000020.11:g.50892526G>A
NG_034200.1:g.43465C>T
NM_001282531.3:c.2188C>TMANE SELECT
NM_001282532.2:c.2188C>T
NM_001347511.2:c.2188C>T
NM_015339.5:c.2188C>T
NM_181442.4:c.2188C>T
NP_001269460.1:p.Arg730Ter
NP_001269461.1:p.Arg730Ter
NP_001334440.1:p.Arg730Ter
NP_056154.1:p.Arg730Ter
NP_852107.1:p.Arg730Ter
NC_000020.10:g.49509063G>A
NM_001282531.1:c.2188C>T
NM_001282531.3:c.2188C>T
NM_015339.2:c.2188C>T
NM_015339.3:c.2188C>T
NM_015339.4:c.2188C>T
NM_181442.3:c.2188C>T
p.Arg730*
p.R730*

Protein change:

R730*

Links:

dbSNP: rs886041116

NCBI 1000 Genomes Browser:

rs886041116

Molecular consequence:

NM_001282531.3:c.2188C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282532.2:c.2188C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001347511.2:c.2188C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_015339.5:c.2188C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_181442.4:c.2188C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Synonyms:: Helsmoortel-Van der Aa Syndrome
Identifiers:: MONDO: MONDO:0014379; MedGen: C4014538; Orphanet: 404448; OMIM: 615873

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000328957	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 30, 2016)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000537697	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 1, 2016)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000894222	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001190485	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 6, 2020)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV001245587	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001428818	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 25, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001445901	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 14, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001832228	GeneReviews	no classification provided	not provided	germline	literature only
SCV004697720	Molecular Genetics Lab, CHRU Brest	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005397762	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 3, 2024)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 35920977, 38282129, 28407407, 38254177, 38204290, 29724491, 35322241, 31029150, 28675391, 27031564, 29475819, 35982159, 35813072, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing, research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	de novo	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Hakim F, Kooy RF, Gozes I.

J Mol Neurosci. 2022 Aug;72(8):1531-1546. doi: 10.1007/s12031-022-02048-0. Epub 2022 Aug 3.

PubMed [citation]

PMID:: 35920977

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, Lobyntseva A, Shazman S, Hakim F, Gozes I.

J Mol Neurosci. 2024 Jan 29;74(1):15. doi: 10.1007/s12031-024-02189-4.

PubMed [citation]

PMID:: 38282129

See all PubMed Citations (14)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues, SCV000328957.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV000537697.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000894222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV001190485.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

Description

ACMG codes: PVS1, PS2, PS4M, PM2, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH, SCV001245587.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	blood	not provided		1	not provided	1	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428818.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

_x000D_This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445901.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV001832228.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

Description

Common pathogenic variant

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics Lab, CHRU Brest, SCV004697720.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center, SCV005397762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 18, 2024

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