Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| SIB Swiss Institute of Bioinformatics | RCV000850490 | SCV001194272 | likely pathogenic | Intellectual developmental disorder 60 with seizures | 2019-12-04 | criteria provided, single submitter | curation | 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. |
| New York Genome Center | RCV001263339 | SCV001441380 | pathogenic | Autism; Seizure; Intellectual disability | 2020-01-28 | criteria provided, single submitter | clinical testing | 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. |
| 3billion | RCV000850490 | SCV002012218 | pathogenic | Intellectual developmental disorder 60 with seizures | 2021-10-02 | criteria provided, single submitter | clinical testing | 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. |
| Revvity Omics, |
RCV000850490 | SCV002021408 | likely pathogenic | Intellectual developmental disorder 60 with seizures | 2021-09-06 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001869288 | SCV002238455 | pathogenic | not provided | 2021-07-02 | criteria provided, single submitter | clinical testing | 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. |
| OMIM | RCV000850490 | SCV000992685 | pathogenic | Intellectual developmental disorder 60 with seizures | 2020-12-11 | no assertion criteria provided | literature only | |
| Molecular Genetics laboratory, |
RCV001869288 | SCV004031313 | pathogenic | not provided | 2021-02-04 | no assertion criteria provided | clinical testing |