Gene Validity Curation

PPP1CB - Noonan syndrome-like disorder with loose anagen hair

Gene: PPP1CB (HGNC:9282)
Classification - 04/23/2020
Disease: Noonan syndrome-like disorder with loose anagen hair (MONDO_0011899)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: RASopathy
Evidence Summary: PPP1CB was first reported in relation to autosomal dominant Noonan syndrome with loose anagen hair (AD NS-LAH) as early as 2016 (Gripp et al., PMID: 27264673). At least 4 unique missense variants (including the recurrent de novo p.Pro49Arg variant) have been reported in humans with this disorder. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 5 publications (PMID: 25356899, 27264673, 27681385, 27868344, 28211982). More evidence is available in the literature, but the maximum score for genetic evidence has been reached (PMID: 30236064). The mechanism of disease is thought to result in more stable/prolonged binding of SHOC2 and PPP1C to MRAS, which is expected to promote a more effective/prolonged RAF p.Ser259 dephosphorylation (PMID: 26446362, 23875798, 16630891). This gene-disease association is supported by relevant experimental evidence implicating a physical association of PP1c (of which PPP1CB is a subunit) with SHOC2, which is definitively associated with NS-LAH (PMID: 16630891, 24211266). The ClinGen RASopathy Expert Panel has assessed PPP1CB for associations with Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, and cardiofaciocutaneous syndrome, however no evidence was reported. In summary, PPP1CB is definitively associated with AD NS-LAH. This curation was approved by the ClinGen RASopathy Expert Panel on 4/23/20 (SOP Version 7).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 9
14
12
Gripp KW et al. 2016 Sep (PMID:27264673); Zambrano RM et al. 2017 Feb (PMID:27868344); Ma L et al. 2016 Dec (PMID:27681385);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
0.5
0.5
Bertola D et al. 2017 Mar (PMID:28211982); Hamdan FF et al. 2014 Oct (PMID:25356899); Ma L et al. 2016 Dec (PMID:27681385);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2 2 0.5
Rodriguez-Viciana P et al. 2006 Apr 21 (PMID:16630891); Young LC et al. 2013 Dec 12 (PMID:24211266);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 0.5 12.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
10/06/2020
EXPERT CURATION (DATE)
Definitive
04/23/2020
EVIDENCE SUMMARY
PPP1CB was first reported in relation to autosomal dominant Noonan syndrome with loose anagen hair (AD NS-LAH) as early as 2016 (Gripp et al., PMID: 27264673). At least 4 unique missense variants (including the recurrent de novo p.Pro49Arg variant) have been reported in humans with this disorder. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 5 publications (PMID: 25356899, 27264673, 27681385, 27868344, 28211982). More evidence is available in the literature, but the maximum score for genetic evidence has been reached (PMID: 30236064). The mechanism of disease is thought to result in more stable/prolonged binding of SHOC2 and PPP1C to MRAS, which is expected to promote a more effective/prolonged RAF p.Ser259 dephosphorylation (PMID: 26446362, 23875798, 16630891). This gene-disease association is supported by relevant experimental evidence implicating a physical association of PP1c (of which PPP1CB is a subunit) with SHOC2, which is definitively associated with NS-LAH (PMID: 16630891, 24211266). The ClinGen RASopathy Expert Panel has assessed PPP1CB for associations with Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, and cardiofaciocutaneous syndrome, however no evidence was reported. In summary, PPP1CB is definitively associated with AD NS-LAH. This curation was approved by the ClinGen RASopathy Expert Panel on 4/23/20 (SOP Version 7).