chr11-66211206-C-T

Variant names:

• chr11-66211206-C-T
• rs398123009
• NM_018026.4:c.607C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 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 (★★). ClinVar reports functional evidence for this variant: "SCV000652987: Experimental studies have shown that this missense change affects PACS1 function (PMID:23159249)." and additional evidence is available in ClinVar.

• 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:55
• Conservation: PhyloP100: 2.35
• Publications: 63 publications found

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]

PACS1 Gene-Disease associations (from GenCC):

• Schuurs-Hoeijmakers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000652987: Experimental studies have shown that this missense change affects PACS1 function (PMID: 23159249).; SCV001984820: "In vivo studies of the p.Arg203Trw 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; SCV002097975: "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; SCV002526408: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23159249)"; SCV002762876: Functional studies demonstrated that this variant forms cytoplasmic aggregates with increased protein stability, consistent with a dominant-negative mechanism (PMID: 23159249) (PS3).; SCV002767838: "In vitro assays demonstrated formation of cytoplasmic aggregates, leading to protein-trafficking defects (PMID: 23159249)."; SCV006074337: "In vivo studies in zebrafish indicate that the variant induces craniofacial defects due to aberrant specification and migration of SOX10-positive neural-crest cells (Schuurs-Hoeijmakers_2012)." PMID: 23159249; SCV000262971: 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).; SCV000299370: 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); PMID: 25533962; SCV001251582: 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.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 39581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018026.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	NM_018026.4	MANE Select	c.607C>T	p.Arg203Trp	missense	Exon 4 of 24	NP_060496.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACS1	ENST00000320580.9	TSL:1 MANE Select	c.607C>T	p.Arg203Trp	missense	Exon 4 of 24	ENSP00000316454.4	Q6VY07-1
	PACS1	ENST00000527380.1	TSL:4	c.313C>T	p.Arg105Trp	missense	Exon 4 of 5	ENSP00000432639.1	E9PPK2
	PACS1	ENST00000533756.5	TSL:4	c.298C>T	p.Arg100Trp	missense	Exon 5 of 5	ENSP00000437150.1	E9PNG7

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251202 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome 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

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111684

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
36	-	-	Schuurs-Hoeijmakers syndrome (36)
11	-	-	not provided (11)
2	-	-	Intellectual disability (2)
1	-	-	Global developmental delay (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	PACS1-related disorder (1)
1	-	-	PACS1-related syndrome (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	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
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

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