ClinVar Genomic variation as it relates to human health
NM_001282531.3(ADNP):c.539_542del (p.Val180fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001282531.3(ADNP):c.539_542del (p.Val180fs)
Variation ID: 373314 Accession: VCV000373314.41
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 20q13.13 20: 50894172-50894175 (GRCh38) [ NCBI UCSC ] 20: 49510709-49510712 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 9, 2017 Oct 8, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001282531.3:c.539_542del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001269460.1:p.Val180fs frameshift NM_001282531.2:c.539_542del NM_001282532.2:c.539_542del NP_001269461.1:p.Val180fs frameshift NM_001347511.2:c.539_542del NP_001334440.1:p.Val180fs frameshift NM_015339.2:c.539_542delTTAG NM_015339.5:c.539_542del NP_056154.1:p.Val180fs frameshift NM_181442.4:c.539_542del NP_852107.1:p.Val180fs frameshift NC_000020.11:g.50894175_50894178del NC_000020.10:g.49510712_49510715del NG_034200.1:g.41816_41819del - Protein change
- V180fs
- Other names
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- Canonical SPDI
- NC_000020.11:50894171:CTAACTA:CTA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ADNP | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
683 | 700 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000413777.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 10, 2015 | RCV000622346.3 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2022 | RCV000626043.13 |
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
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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
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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
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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. |
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Pathogenic
(Aug 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746661.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Short stature (present) , Renal duplication (present) , Relative macrocephaly (present) , Poor suck (present) , Pes planus (present) , Patent foramen ovale (present) , … (more)
Short stature (present) , Renal duplication (present) , Relative macrocephaly (present) , Poor suck (present) , Pes planus (present) , Patent foramen ovale (present) , Congenital omphalocele (present) , Oligohydramnios (present) , Micrognathia (present) , Hypoplasia of facial musculature (present) , Growth delay (present) , Global developmental delay (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Feeding difficulties in infancy (present) , Esotropia (present) , Downslanted palpebral fissures (present) , Decreased fetal movement (present) , Congenital hypothyroidism (present) , Autistic disorder of childhood onset (present) , Anal stenosis (present) , Abnormality of the trachea (present) , Abnormality of the ear (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: White
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-08-02
Testing laboratory interpretation: Pathogenic
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141253.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447513.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Absent speech (present) , Motor delay (present) , Hypotonia (present) , Severe global developmental delay (present)
Sex: female
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Pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Affected status: yes
Allele origin:
de novo
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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515278.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 10, 2015)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740905.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Behavioral abnormality (present) , Ventricular septal defect (present) , Short stature (present) , Toe walking (present) , Delayed speech and … (more)
Global developmental delay (present) , Behavioral abnormality (present) , Ventricular septal defect (present) , Short stature (present) , Toe walking (present) , Delayed speech and language development (present) , Relative macrocephaly (present) , Frontal bossing (present) , Hypertelorism (present) , Abnormality of the helix (present) , Low-set ears (present) , Wide nasal bridge (present) , Thin upper lip vermilion (present) , Smooth philtrum (present) , Inappropriate laughter (present) , Recurrent hand flapping (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Feb 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Helsmoortel-Van der Aa Syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001251635.2
First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023 |
Comment:
The ADNP c.539_542delTTAG (p.Val180GlyfsTer17) variant is a frameshift variant that has been identified in one study, in which it is found in a de novo … (more)
The ADNP c.539_542delTTAG (p.Val180GlyfsTer17) variant is a frameshift variant that has been identified in one study, in which it is found in a de novo heterozygous state in one individual with ADNP-related neurodevelopmental disorder (Bend et al. 2019). The p.Val180GlyfsTer17 variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the potential impact of truncating variants in this gene, its rarity, its identification in a patient in the literature, and application of the ACMG criteria, the p.Val180GlyfsTer17 variant is classified as pathogenic for ADNP-related neurodevelopmental disorder. (less)
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Pathogenic
(May 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Affected status: yes
Allele origin:
germline
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Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV003836737.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, University of Torino
Accession: SCV004171082.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443840.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val180Glyfs*17) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Val180Glyfs*17) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 923 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 clinical features of Helsmoortel-Van der Aa syndrome (PMID: 28675391, 31029150). ClinVar contains an entry for this variant (Variation ID: 373314). This variant disrupts a region of the ADNP protein in which other variant(s) (p.Tyr719*) have been determined to be pathogenic (PMID: 28221363, 28708303, 29911927). 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. (less)
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000491899.4
First in ClinVar: Jan 09, 2017 Last updated: Sep 29, 2024 |
Comment:
Frameshift variant predicted to result in abnormal protein length as the last 923 amino acids are replaced with 16 different amino acids, and other similar … (more)
Frameshift variant predicted to result in abnormal protein length as the last 923 amino acids are replaced with 16 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29724491, 31029150, 35904121, 33860439, 35982159, 31785789, 36474027, 32758449, 31526516, Aspromonte2023[pre-print], 36553633, 28221363) (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502398.22
First in ClinVar: Mar 14, 2021 Last updated: Oct 08, 2024 |
Comment:
ADNP: PS2, PVS1:Strong, PM2, PS4:Moderate
Number of individuals with the variant: 2
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome. | Bend EG | Clinical epigenetics | 2019 | PMID: 31029150 |
Mutations in ADNP affect expression and subcellular localization of the protein. | Cappuyns E | Cell cycle (Georgetown, Tex.) | 2018 | PMID: 29911927 |
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients. | Chérot E | Clinical genetics | 2018 | PMID: 28708303 |
Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children. | Gozes I | Translational psychiatry | 2017 | PMID: 28675391 |
Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children. | Gozes I | Translational psychiatry | 2017 | PMID: 28221363 |
Text-mined citations for rs1057518345 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.