ClinVar Miner

Submissions for variant NM_002709.3(PPP1CB):c.146C>G (p.Pro49Arg) (rs886037952)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000257986 SCV000299373 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing The P49R variant in the PPP1CB gene has been reported previously as a de novo variant in three unrelated individuals with macrocephaly, developmental delay, and dysmorphic features as well as variable additional features including short stature and congenital heart defects (Gripp et al., 2016). The P49R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P49R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P49R as a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000257986 SCV000609586 pathogenic not provided 2017-08-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000257986 SCV000861880 pathogenic not provided 2018-06-15 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000257986 SCV000928041 pathogenic not provided 2018-11-07 criteria provided, single submitter clinical testing
Invitae RCV000257986 SCV000933113 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 49 of the PPP1CB protein (p.Pro49Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the literature in individuals affected with Noonan syndrome-like disorder with loose anagen hair (NSLDH) (PMID: 27681385, 28211982) and also been observed to be de novo in individuals affected with NSLDH (PMID: 27264673, 27681385, 27868344). ClinVar contains an entry for this variant (Variation ID: 254648). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000490622 SCV000579309 pathogenic Noonan syndrome-like disorder with loose anagen hair 2 2017-05-31 no assertion criteria provided literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000490622 SCV001190249 pathogenic Noonan syndrome-like disorder with loose anagen hair 2 2019-05-04 no assertion criteria provided clinical testing

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