ClinVar Miner

Submissions for variant NM_018026.3(PACS1):c.607C>T (p.Arg203Trp) (rs398123009)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190758 SCV000244199 pathogenic Multiple congenital anomalies criteria provided, single submitter clinical testing POSITIVE: Relevant Alteration(s) Detected
Ambry Genetics RCV000210719 SCV000262971 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Miraca Genetics Laboratories, RCV000032781 SCV000328721 pathogenic Schuurs-hoeijmakers syndrome 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found four times in our laboratory de novo in males with ID/DD, dysmorphisms, epilepsy, colobomas in 2 and CHD in 2
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735338 SCV000854492 pathogenic Hypotelorism; Horseshoe kidney; Optic disc pallor; Mitral valve prolapse; Aortic root dilatation criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000429725 SCV000511283 pathogenic not provided 2016-07-07 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000032781 SCV000244000 likely pathogenic Schuurs-hoeijmakers syndrome 2013-06-27 no assertion criteria provided literature only
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000032781 SCV000700152 pathogenic Schuurs-hoeijmakers syndrome 2017-01-12 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000032781 SCV000611290 pathogenic Schuurs-hoeijmakers syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000429725 SCV000299370 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing The R203W pathogenic variant in the PACS1 gene has been reported previously in multiple unrelated patients with intellectual disability, dysmorphic features, hypotonia, seizures, and structural malformations (Schuurs-Hoeijmakers et al., 2016; Stern et al., 2017). The R203W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R203W variant is a non-conservative amino acid substitution, which occurs at a residue that is conserved across species. 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). We interpret R203W as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000032781 SCV000596192 pathogenic Schuurs-hoeijmakers syndrome 2016-07-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000032781 SCV000743593 pathogenic Schuurs-hoeijmakers syndrome 2017-07-28 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000032781 SCV000745741 pathogenic Schuurs-hoeijmakers syndrome 2015-11-23 no assertion criteria provided clinical testing
HudsonAlpha Institute for Biotechnology RCV000032781 SCV000265589 pathogenic Schuurs-hoeijmakers syndrome 2017-04-13 criteria provided, single submitter research
Invitae RCV000032781 SCV000652987 pathogenic Schuurs-hoeijmakers syndrome 2017-08-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 203 of the PACS1 protein (p.Arg203Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs398123009, ExAC 0.01%). This variant has been reported to be de novo in many individuals affected with intellectual disability and/or epilepsy (PMID: 26795593, 26842493). ClinVar contains an entry for this variant (Variation ID: 39581). Experimental studies have shown that this missense change triggers PACS1 cytoplasmic aggregates, leads to protein-trafficking defects and abrogates normal protein function of PACS1 in vivo and in vitro (PMID: 23159249). For these reasons, this variant has been classified as Pathogenic.
Laboratoire de Cytogenetique,Hospices Civils de Lyon RCV000032781 SCV000890089 pathogenic Schuurs-hoeijmakers syndrome 2017-03-10 criteria provided, single submitter clinical testing
OMIM RCV000032781 SCV000056545 pathogenic Schuurs-hoeijmakers syndrome 2012-12-07 no assertion criteria provided literature only

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