GeneBe

rs1555408401

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001100913.3(PACS2):​c.625G>A​(p.Glu209Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

PACS2
NM_001100913.3 missense

Scores

5
8
6

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36

Conservation

PhyloP100: 9.67
Variant links:
Genes affected
PACS2 (HGNC:23794): (phosphofurin acidic cluster sorting protein 2) Predicted to enable transmembrane transporter binding activity. Involved in endoplasmic reticulum calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and protein localization to plasma membrane. Acts upstream of or within protein localization to phagophore assembly site. Located in endoplasmic reticulum and mitochondrion. Implicated in developmental and epileptic encephalopathy 66. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-105368112-G-A is Pathogenic according to our data. Variant chr14-105368112-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-105368112-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PACS2NM_001100913.3 linkc.625G>A p.Glu209Lys missense_variant Exon 6 of 25 ENST00000447393.6 NP_001094383.2 Q86VP3-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PACS2ENST00000447393.6 linkc.625G>A p.Glu209Lys missense_variant Exon 6 of 25 1 NM_001100913.3 ENSP00000393559.2 Q86VP3-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:36
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 66 Pathogenic:21
Mar 04, 2025
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS2,PS4,PM1_STR_VSTR,PS3_SUP,PM2 -

Sep 08, 2002
Center of Excellence for Medical Genomics, Chulalongkorn University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PS4+PS2+PP4+PS3_Supporting -

Dec 12, 2018
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 01, 2022
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.23; 3Cnet: 0.20). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495141). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29656858). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29656858). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2022
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 08, 2023
Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Oct 14, 2021
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS3, PM1, PM2, PP3, PP5 -

Mar 14, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Nov 24, 2020
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Oct 09, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function has been suggested (PMID: 29656858). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variability of clinical severity has been reported in a family (PMID: 35770754). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in many clinical testing laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 16, 2022
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2019
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

-
Lifecell International Pvt. Ltd
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A Heterozygous Missense variant c.625G>A in Exon 6 of the PACS2 gene that results in the amino acid substitution p.Glu209Lys was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variation ID: 495141). The variant has been previously reported for Developmental and epileptic encephalopathy by Olson HE, et al., 2018. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function (Olson HE, et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PS4, PS2, PP4, PM2, PS3 -

Jul 07, 2020
Center for Molecular Medicine, Children’s Hospital of Fudan University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 20, 2024
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 26, 2024
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:8
Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PACS2: PS2:Very Strong, PS4, PM2, PS3:Supporting -

Jun 21, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 06, 2019
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the PACS2 protein (p.Glu209Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PACS2-related conditions (PMID: 29656858). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 495141). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Apr 29, 2020
AiLife Diagnostics, AiLife Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 16, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28628100, 29656858, 28867141, 28135719, 30684285, 32416568, 32166392, 28191890, 30290155, 30904718, 31231135, 31036916, 25741868, 31130284, 34489640, 33243487, 33240318, 33461828, 33004838) -

Jul 29, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP4, PM2, PS2_very_strong, PS4 -

Jan 20, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS2_very_strong, PS3, PS4, PM2 -

PACS2-related disorder Pathogenic:2
Sep 19, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PACS2 c.625G>A variant is predicted to result in the amino acid substitution p.Glu209Lys. This variant has been documented in a large number of cases as a recurrent de novo cause of disease and the defining pathogenic variant in PACS2 (see for example, Olson et al. 2018. PubMed ID: 30290155). In vitro analysis in the Olson study indicated that this variant disrupts autoregulation and companion protein interactions. This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Sep 10, 2024
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.625G>A (p.Glu209Lys) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This is a recurrent, known Pathogenic variant that has been previously reported as a heterozygous change in patients with developmental and epileptic encephalopathy (PMID: 29656858, 30684285, 32416568, 33243487, 34253499, 34894068, 36188273, 35770754). Functional studies indicate that the c.625G>A (p.Glu209Lys) variant alters binding of PACS2 to one or more of its interacting proteins critical for neurogenesis, neuronal communication, and cerebellar development (PMID: 29656858, 36188273).The c.625G>A (p.Glu209Lys) variant is absent from the latest version of the gnomAD population database and thus is presumed to be rare. Based on parental analysis, this variant likely occurred as a de novo event. Based on the available evidence, c.625G>A (p.Glu209Lys) is classified as Pathogenic. -

Developmental and epileptic encephalopathy, 1 Pathogenic:1
Jan 05, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.625G>A;p.(Glu209Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 495141; OMIM: 610423.0001; PMID: 29656858) - PS4.This variant is not present in population databases (rs1555408401, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 29656858) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. -

Inborn genetic diseases Pathogenic:1
Apr 16, 2018
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Pathogenic:1
Apr 26, 2021
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP5_very strong;PM2_supporting;PP2_supporting -

Intellectual disability Pathogenic:1
Aug 05, 2016
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Seizure Pathogenic:1
Jul 13, 2022
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.051
T
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.51
.;D;.;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.53
D;D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Pathogenic
3.1
.;M;M;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.0
D;D;D;D
REVEL
Benign
0.23
Sift
Benign
0.042
D;T;T;T
Sift4G
Uncertain
0.039
D;T;T;D
Polyphen
0.76, 0.96
.;P;D;.
Vest4
0.75
MutPred
0.20
.;Gain of ubiquitination at E209 (P = 0);Gain of ubiquitination at E209 (P = 0);.;
MVP
0.24
ClinPred
0.96
D
GERP RS
4.1
Varity_R
0.50
gMVP
0.26

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555408401; hg19: chr14-105834449; COSMIC: COSV100330680; COSMIC: COSV100330680; API