This variant is interpreted as Likely pathogenic for Intellectual developmental disorder 60 with seizures, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PS3-Moderate, PS4-Supporting, PP3, PP2.
ClinVar Genomic variation as it relates to human health
NM_004068.4(AP2M1):c.508C>T (p.Arg170Trp)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004068.4(AP2M1):c.508C>T (p.Arg170Trp)
Variation ID: 689722 Accession: VCV000689722.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q27.1 3: 184180927 (GRCh38) [ NCBI UCSC ] 3: 183898715 (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 Sep 22, 2019 Oct 8, 2024 Feb 20, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004068.4:c.508C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004059.2:p.Arg170Trp missense NM_001025205.1:c.502C>T NM_001025205.2:c.502C>T NP_001020376.1:p.Arg168Trp missense NM_001311198.1:c.583C>T NM_001311198.2:c.583C>T NP_001298127.1:p.Arg195Trp missense NC_000003.12:g.184180927C>T NC_000003.11:g.183898715C>T - Protein change
- R170W, R168W, R195W
- Other names
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- Canonical SPDI
- NC_000003.12:184180926:C:T
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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
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| AP2M1 | - | - |
GRCh38 GRCh37 |
212 | 272 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2021 | RCV000850490.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 28, 2020 | RCV001263339.3 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 20, 2023 | RCV001869288.10 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Dec 04, 2019)
|
criteria provided, single submitter
Method: curation
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Intellectual developmental disorder 60 with seizures
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV001194272.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
This variant is interpreted as Likely pathogenic for Intellectual developmental disorder 60 with seizures, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PS3-Moderate, … (more)
This variant is interpreted as Likely pathogenic for Intellectual developmental disorder 60 with seizures, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PS3-Moderate, PS4-Supporting, PP3, PP2. (less)
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Pathogenic
(Jan 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Seizure
Intellectual disability Autism (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001441380.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Comment:
The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene substitutes a completely conserved Arginine for Tryptophan at amino acid 170/436 (coding exon 6/12). This variant … (more)
The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene substitutes a completely conserved Arginine for Tryptophan at amino acid 170/436 (coding exon 6/12). This variant is absent from gnomAD suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score: -5.70) and Damaging (SIFT; score: 0.000) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:689722) based on literature evidence. The c.508C>T (p.Arg170Trp) variant has been identified de novo in 4 individuals with Intellectual Developmental Disorder with Seizures [PMID: 31104773]. Functional analysis of the p.Arg170Trp variant suggests it impairs clathrin dependent endocytosis, possibly via altered recognition potential of cargo membrane proteins [PMID: 31104773]. This variant was identified de novo in an individual submitted for clinical WGS testing. The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene is reported here as Pathogenic. (less)
Secondary finding: no
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Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder 60 with seizures
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV002012218.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individuals (PMID: 31104773, PS2, PS4_M). … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individuals (PMID: 31104773, PS2, PS4_M). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 31104773 ). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Epicanthus (present) , Seizure (present) , Hirsutism (present) , Midface retrusion (present) , Thick eyebrow (present) , Fair hair (present) , Macrotia (present)
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Likely pathogenic
(Sep 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder 60 with seizures
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021408.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 02, 2021)
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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: SCV002238455.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine with tryptophan at codon 170 of the AP2M1 protein (p.Arg170Trp). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with tryptophan at codon 170 of the AP2M1 protein (p.Arg170Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of AP2M1-related conditions (PMID: 31104773). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 689722). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant affects AP2M1 protein function (PMID: 31104773). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Feb 20, 2023)
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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: SCV005327813.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
Identified as a recurrent de novo variant in four individuals with developmental and epileptic encephalopathies with features including global developmental delay, seizures, ataxic gait, hypotonia, … (more)
Identified as a recurrent de novo variant in four individuals with developmental and epileptic encephalopathies with features including global developmental delay, seizures, ataxic gait, hypotonia, and moderate to severe intellectual disability in published literature; referred to as R170W due to the use of alternative nomenclature (Helbig et al., 2019); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31104773, 31671891, 33225555, 32743075) (less)
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Pathogenic
(Dec 11, 2020)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 60, WITH SEIZURES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000992685.2
First in ClinVar: Sep 22, 2019 Last updated: Dec 19, 2020 |
Comment on evidence:
In 4 unrelated girls with autosomal dominant intellectual developmental disorder-60 with seizures (MRD60; 618587), Helbig et al. (2019) identified a de novo heterozygous c.508C-T transition … (more)
In 4 unrelated girls with autosomal dominant intellectual developmental disorder-60 with seizures (MRD60; 618587), Helbig et al. (2019) identified a de novo heterozygous c.508C-T transition (c.508C-T, NM_004068.3) in the AP2M1 gene, resulting in an arg170-to-trp (R170W) substitution within a basic phospholipid-binding patch that is thought to stabilize the active open conformation of AP2 to aid in the association with cargo membrane proteins. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD or ExAC databases. Molecular modeling suggested that the mutation caused increased entropy in both the open and closed conformations of the AP2 complex, consistent with thermodynamic instability. In vitro functional expression studies in AP2M1-null HeLa cells and Ap2m1-null mouse astrocytes showed that the R170W variant caused reduced endocytosis compared to wildtype AP2M1, suggesting that the mutation adversely affects clathrin-mediated endocytosis, possibly by impaired recognition of cargo membrane proteins. The mutant protein was expressed at normal levels and localized properly to clathrin-coated pits. (less)
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Pathogenic
(Feb 04, 2021)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
de novo
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Molecular Genetics laboratory, Necker Hospital
Accession: SCV004031313.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Clinical Features:
Intellectual disability (present)
|
Comment:
Comment:
The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene substitutes a completely conserved Arginine for Tryptophan at amino acid 170/436 (coding exon 6/12). This variant is absent from gnomAD suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score: -5.70) and Damaging (SIFT; score: 0.000) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:689722) based on literature evidence. The c.508C>T (p.Arg170Trp) variant has been identified de novo in 4 individuals with Intellectual Developmental Disorder with Seizures [PMID: 31104773]. Functional analysis of the p.Arg170Trp variant suggests it impairs clathrin dependent endocytosis, possibly via altered recognition potential of cargo membrane proteins [PMID: 31104773]. This variant was identified de novo in an individual submitted for clinical WGS testing. The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene is reported here as Pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individuals (PMID: 31104773, PS2, PS4_M). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 31104773 ). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine with tryptophan at codon 170 of the AP2M1 protein (p.Arg170Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of AP2M1-related conditions (PMID: 31104773). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 689722). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant affects AP2M1 protein function (PMID: 31104773). For these reasons, this variant has been classified as Pathogenic.
Comment:
Identified as a recurrent de novo variant in four individuals with developmental and epileptic encephalopathies with features including global developmental delay, seizures, ataxic gait, hypotonia, and moderate to severe intellectual disability in published literature; referred to as R170W due to the use of alternative nomenclature (Helbig et al., 2019); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31104773, 31671891, 33225555, 32743075)
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:
This variant is interpreted as Likely pathogenic for Intellectual developmental disorder 60 with seizures, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PS3-Moderate, PS4-Supporting, PP3, PP2.
Comment:
The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene substitutes a completely conserved Arginine for Tryptophan at amino acid 170/436 (coding exon 6/12). This variant is absent from gnomAD suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score: -5.70) and Damaging (SIFT; score: 0.000) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:689722) based on literature evidence. The c.508C>T (p.Arg170Trp) variant has been identified de novo in 4 individuals with Intellectual Developmental Disorder with Seizures [PMID: 31104773]. Functional analysis of the p.Arg170Trp variant suggests it impairs clathrin dependent endocytosis, possibly via altered recognition potential of cargo membrane proteins [PMID: 31104773]. This variant was identified de novo in an individual submitted for clinical WGS testing. The c.508C>T (p.Arg170Trp) variant identified in the AP2M1 gene is reported here as Pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individuals (PMID: 31104773, PS2, PS4_M). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 31104773 ). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine with tryptophan at codon 170 of the AP2M1 protein (p.Arg170Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of AP2M1-related conditions (PMID: 31104773). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 689722). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant affects AP2M1 protein function (PMID: 31104773). For these reasons, this variant has been classified as Pathogenic.
Comment:
Identified as a recurrent de novo variant in four individuals with developmental and epileptic encephalopathies with features including global developmental delay, seizures, ataxic gait, hypotonia, and moderate to severe intellectual disability in published literature; referred to as R170W due to the use of alternative nomenclature (Helbig et al., 2019); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31104773, 31671891, 33225555, 32743075)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. | Helbig I | American journal of human genetics | 2019 | PMID: 31104773 |
Text-mined citations for rs1577059692 ...
HelpThese 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 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.