chr11-66211206-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_018026.4(PACS1):​c.607C>T​(p.Arg203Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PACS1
NM_018026.4 missense

Scores

10
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:52

Conservation

PhyloP100: 2.35
Variant links:
Genes affected
PACS1 (HGNC:30032): (phosphofurin acidic cluster sorting protein 1) This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.792
PP5
Variant 11-66211206-C-T is Pathogenic according to our data. Variant chr11-66211206-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66211206-C-T is described in Lovd as [Pathogenic]. Variant chr11-66211206-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PACS1NM_018026.4 linkc.607C>T p.Arg203Trp missense_variant Exon 4 of 24 ENST00000320580.9 NP_060496.2 Q6VY07-1A0A024R5H6
PACS1XM_011545162.2 linkc.313C>T p.Arg105Trp missense_variant Exon 4 of 24 XP_011543464.2
PACS1XM_011545164.3 linkc.268C>T p.Arg90Trp missense_variant Exon 4 of 24 XP_011543466.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PACS1ENST00000320580.9 linkc.607C>T p.Arg203Trp missense_variant Exon 4 of 24 1 NM_018026.4 ENSP00000316454.4 Q6VY07-1
PACS1ENST00000527380.1 linkc.313C>T p.Arg105Trp missense_variant Exon 4 of 5 4 ENSP00000432639.1 E9PPK2
PACS1ENST00000533756.5 linkc.298C>T p.Arg100Trp missense_variant Exon 5 of 5 4 ENSP00000437150.1 E9PNG7
PACS1ENST00000527224.1 linkn.731C>T non_coding_transcript_exon_variant Exon 4 of 7 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461438
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727020
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:52
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Schuurs-Hoeijmakers syndrome Pathogenic:35
Feb 23, 2023
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 07, 2012
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: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with Schuurs-Hoeijmakers syndrome (MIM#615009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg203Gln) has been observed as a de novo variant in a patient with Schuurs-Hoeijmakers syndrome (PMID: 28975623). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported to be de novo in more than twenty individuals with Schuurs-Hoeijmakers syndrome (ClinVar, PMID: 23159249, 25522177, 26842493). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated formation of cytoplasmic aggregates, leading to protein-trafficking defects (PMID: 23159249). (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 -

Jul 17, 2020
Service de Génétique Moléculaire, Hôpital Robert Debré
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 27, 2020
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The de novo p.Arg203Trp variant identified in PACS1 is a known pathogenic recurrent de novo variant that has been reported in multiple affected individuals in the literature [PMID: 26842493; PMID: 23159249; PMID: 25522177]. The variant has been reported in the ClinVar database by multiple laboratories and is classified as pathogenic (ClinVar Variation ID: 39581). The p.Arg203Trp variant has 0.000007 allele frequency in the gnomAD(V3) database (1 out of 143,260 heterozygous alleles) indicating it is not a common benign variant in the populations represented in that database. The variant affects a highly conserved residue and is predicted deleterious by multiple in silico prediction tools. In vitro functional studies have shown that the p.Arg203Trp variant forms cytoplasmic aggregates resulting in defective protein trafficking, suggestive of a dominant-negative mechanism of disease [PMID: 23159249]. Based on the available evidence, the p.Arg203Trp variant in the PACS1 gene is assessed as Pathogenic. -

-
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 14, 2019
GenomeConnect - Simons Searchlight
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-01-14 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

Jun 05, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 29, 2020
Breda Genetics srl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant c.607C>T (p.Arg203Trp) in PACS1 is reported as pathogenic for Schuurs-Hoeijmakers syndrome in ClinVar (Variation ID: 39581) and as affects function in the Global Variome shared LOVD database v.3.0. There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The nucleotide position is conserved across 35 mammalian species (GERP RS: 4.79). In silico analysis indicates that the variant might be damaging. This mutation has been firstly reported by Schuurs-Hoeijmakers et al. (2012) in 2 unrelated boys with mental retardation and a strikingly similar facial appearance. Later, different other groups reported the same de novo recurrent pathogenic variant in patients with a similar phenotype (Gadzicki et al., 2015; Martinez-Monseny et al.,2018; Dutta et al., 2019 and many others). -

Jul 20, 2016
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 02, 2021
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported at least twice as de novoo in similarly affected indivisual (PMID: 25533962, 23159249, PS2, PS4_M). 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. -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP2,PP3. -

May 11, 2021
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 28, 2017
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 27, 2013
ClinVar Staff, National Center for Biotechnology Information (NCBI)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 04, 2020
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

This variant has been previously reported as a recurrent de novo change in patients with seizures, dysmorphic features, gastroesophageal reflux, cardiac abnormalities, intellectual disability, speech delay, (PMID: 28111752, 26842493). In vivo studies of the p.Arg203Trp variant in zebrafish embryos observed that it induces craniofacial defects, most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells (PMID: 23159249). It is absent from the gnomAD population database and thus is presumed to be rare. The c.607C>T (p.Arg203Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.607C>T (p.Arg203Trp) variant is classified as Pathogenic. -

Oct 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 203 of the PACS1 protein (p.Arg203Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or epilepsy (PMID: 26795593, 26842493). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39581). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PACS1 protein function. Experimental studies have shown that this missense change affects PACS1 function (PMID: 23159249). For these reasons, this variant has been classified as Pathogenic. -

Nov 23, 2015
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 02, 2020
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jan 16, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2 -

Apr 13, 2017
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

May 13, 2021
Pediatric Genetics Clinic, Sheba Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 20, 2022
Eurofins-Biomnis
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 30, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 14, 2021
Laboratory of Medical Genetics, University of Torino
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

-
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 01, 2023
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 10, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.607C>T;p.(Arg203Trp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 39581; PMID: 23159249; 25522177; 26795593; 26842493; 28111752; 30588754) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23159249) - PS3_supporting. The variant is present at low allele frequencies population databases (rs398123009– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 23159249; 25522177; 33166031) PM6_strong. In summary, the currently available evidence indicates that the variant is Pathogenic -

-
Wangler Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense PACS1 variant at c.607C>T (p.R203W) variant in the PACS1 was seen on exome through the Texome project (R01HG011795) as a de novo variant in the patient (PS2). This recurrent de novo variant has been previously reported in more than 20 individuals with Schuurs-Hoeijmakers syndrome (PMID: 26842493, 30588754). This variant has not been observed in gnomAD (PM2). Functional studies demonstrated that this variant forms cytoplasmic aggregates with increased protein stability, consistent with a dominant-negative mechanism (PMID: 23159249) (PS3). This variant has a deleterious prediction score (CADD: 29.4) (PP3), and the evolutionary conservation of this residue is high. We classify this variant as pathogenic. -

Dec 19, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 18, 2017
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 10, 2017
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

PS2,PS4,PM2,PP3 -

Dec 13, 2022
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 10, 2023
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:9
Nov 11, 2016
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 15, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies indicate that the R203W variant perturbs normal PACS1 function by forming cytoplasmic aggregates, resulting in altered protein-trafficking, possibly suggesting a dominant-negative effect on the protein (Schuurs-Hoeijmakers et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25533962, 28135719, 25356970, 27959697, 26842493, 29656858, 23159249, 26795593, 26944241, 28111752, 28554332, 28628100, 28867141, 27875746, 30690871, 30588754, 30113927, 31330568, 25522177, 28975623, 28471432, 31988453, 30577886, 32963807, 33166031, 33333793, 30755392, 33144682, 32903913, 33726816, 34068396, 31785789) -

Feb 08, 2023
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS4, PM2_SUP, PP2 -

May 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Global developmental delay Pathogenic:1
Nov 01, 2019
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

HP:0000085 (present);na:HP:0000543 (present);na:HP:0000601 (present);na:HP:0001634 (present);na:HP:0002616 (present) Pathogenic:1
Nov 19, 2018
Center for Personalized Medicine, Children's Hospital Los Angeles
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Oct 04, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.607C>T (p.R203W) alteration is located in coding exon 4 of the PACS1 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the arginine (R) at amino acid position 203 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/152152) total alleles studied. The highest observed frequency was 0.002% (1/41434) of African/African American alleles. This one allele was reported with low allele balance (0.2-0.25). This recurrent de novo alteration has been reported in multiple individuals with Schuurs-Hoeijmakers syndrome, with commonly reported features including developmental delay/intellectual disability, dysmorphic facial features, seizures, and other congenital malformations (Schurrs-Hoeijmakers, 2016; Deciphering Developmental Disorders Study, 2017; Stern, 2017; Gadzicki, 2015; Tenorio-Casta&ntilde;o, 2021). This amino acid position is highly conserved in available vertebrate species. The p.R203W substitution is positioned in the furin (cargo)-binding region of PACS1, which lies directly adjacent to the R196RKRY CK2-binding motif. This motif regulates phosphorylation status of the autoregulatory domain and PACS1 gene activation (Shuurs-Hoeijmakers, 2012). Functional analysis in zebrafish embryos with overexpression of mutant mRNA with this alteration demonstrated a significant reduction in cranial cartilaginous structures at the ventral aspect. In addition, overexpression of this altered protein resulted in defective migration of cranial-neural-crest cells in the head. Studies in human embryonic kidney cells demonstrated that expression of mutant PACS1 remains more stable than the wild-type protein leading to observed cellular aggregates (Shuurs-Hoeijmakers, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

PACS1-related disorder Pathogenic:1
May 14, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PACS1 c.607C>T variant is predicted to result in the amino acid substitution p.Arg203Trp. This variant has been reported as a recurrent de novo alteration in several individuals with Schuurs-Hoeijmakers syndrome and is considered one of the defining variants of this disorder (Schuurs-Hoeijmakers et al. 2012. PubMed ID: 23159249; Seto et al. 2020. PubMed ID: 33166031). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

PACS1-related syndrome Pathogenic:1
Feb 05, 2020
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Across a selection of available literature, the PACS1 c.607C>T (p.Arg203Trp) missense variant has been found in a heterozygous state in at least 35 individuals with PACS1-related Syndrome (Schuurs-Hoeijmakers et al. 2012; Farwell et al. 2015; Schuurs-Hoeijmakers et al. 2016, Lazaridis et al. 2016; Stern et al. 2017; Tarailo-Graovac et al. 2017; Bowling et al. 2017; Geisheker et al. 2017; Pefkianaki et al. 2018; Dutta et al. 2019). This variant was identified as de novo in the affected individuals in all instances where parental samples were available. Control data are unavailable for this variant, which is absent from the Genome Aggregation Database in an area of good sequencing coverage, so the variant is presumed to be rare. Expression of the variant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al. 2012). The authors also showed that the p.Arg203Trp variant results in the formation of cytoplasmic aggregates and altered protein trafficking, and suggested a dominant-negative affect on the protein. Based on the collective evidence, the p.Arg203Trp variant is classified as pathogenic for PACS1-related syndrome. -

See cases Pathogenic:1
Dec 07, 2021
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PM2, PM6, PP2 -

Neurodevelopmental disorder Pathogenic:1
Nov 07, 2022
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Intellectual disability Pathogenic:1
Mar 08, 2021
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Recurrent pathogenics PACS1 variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.53
D;.;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.5
M;.;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-6.8
D;D;D
REVEL
Uncertain
0.44
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.97
MutPred
0.48
Gain of sheet (P = 0.0221);.;.;
MVP
0.83
MPC
2.4
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.74
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs398123009; hg19: chr11-65978677; COSMIC: COSV57698895; COSMIC: COSV57698895; API