chr11-66211206-C-T

Position:

• chr11-66211206-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:51
• Conservation: PhyloP100: 2.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PACS1. . Gene score misZ 3.71 (greater than the threshold 3.09). Trascript score misZ 3.8723 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Schuurs-Hoeijmakers syndrome.
• 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/exons	MANE	Protein	UniProt
PACS1	NM_018026.4	c.607C>T	p.Arg203Trp	missense_variant	4/24	ENST00000320580.9	NP_060496.2
PACS1	XM_011545162.2	c.313C>T	p.Arg105Trp	missense_variant	4/24		XP_011543464.2
PACS1	XM_011545164.3	c.268C>T	p.Arg90Trp	missense_variant	4/24		XP_011543466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS1	ENST00000320580.9	c.607C>T	p.Arg203Trp	missense_variant	4/24	1	NM_018026.4	ENSP00000316454	P2
PACS1	ENST00000527380.1	c.313C>T	p.Arg105Trp	missense_variant	4/5	4		ENSP00000432639
PACS1	ENST00000533756.5	c.298C>T	p.Arg100Trp	missense_variant	5/5	4		ENSP00000437150
PACS1	ENST00000527224.1	n.731C>T		non_coding_transcript_exon_variant	4/7	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

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

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:51

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schuurs-Hoeijmakers syndrome Pathogenic:33

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jun 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a tryptophan (exon 4). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. Another variant in the same location p.(Arg203Gln), was found to be de novo in a patient with Schuurs-Hoeijmakers syndrome (PMID: 28975623). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported to be de novo in more than 20 patients with Schuurs-Hoeijmakers syndrome (PMID: 23159249, 25522177, 26842493; ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated formation of cytoplasmic aggregates, leading to protein-trafficking defects (PMID:23159249). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 30, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	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). Advanced 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 at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Mar 10, 2017	- -
Pathogenic, criteria provided, single submitter	research	Department of Paediatrics and Adolescent Medicine, The University of Hong Kong	Jun 02, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 13, 2017	- -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Jan 14, 2019	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. -
Likely pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Jul 29, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 27, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 16, 2024	Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Medical Genetics, University of Torino	Mar 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 04, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	May 11, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Oct 20, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	Jul 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Feb 08, 2023	PS4, PM2_SUP, PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -

See cases Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 07, 2021	ACMG classification criteria: PS3, PS4, PM2, PM6, PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Personalized Medicine, Children's Hospital Los Angeles	Dec 21, 2022	- -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Nov 01, 2019

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

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-Castaño, 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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2020

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. -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Nov 07, 2022

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Mar 08, 2021

Recurrent pathogenics PACS1 variant. -

Mitral valve prolapse;C0221353:Horseshoe kidney;C0424711:Hypotelorism;C0554970:Optic disc pallor;C1298820:Aortic root aneurysm Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

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;.;.
MutationTaster	Benign	1.0	D
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

Other links and lift over

dbSNP: rs398123009; hg19: chr11-65978677; COSMIC: COSV57698895; COSMIC: COSV57698895;