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

dbSNP: rs886037952

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV004732471	SCV005367861	pathogenic	RASopathy	2024-09-17	reviewed by expert panel	curation	The c.146C>G (Pro49Arg) variant in PPP1CB is a missense variant predicted to cause substitution of proline by arginine at amino acid 49. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.438, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 13 probands with features of RASopathy (PS4; PMIDs: 27264673, 27681385, 27868344, 28211982, 30368668, 32476286). This variant has been identified as a de novo occurrence with confirmed parental relationships in 9 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 27264673, 27681385, 27868344). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VS, PS4, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024)
GeneDx	RCV000257986	SCV000299373	pathogenic	not provided	2021-10-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27264673, 27868344, 27338287, 28211982, 27681385, 28135719, 30368668, 31474318, 31370276, 32476286)
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
Eurofins Ntd Llc (ga)	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257986	SCV000933113	pathogenic	not provided	2023-01-07	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Noonan syndrome-like disorder with loose anagen hair (NSLDH) (PMID: 27264673, 27681385, 27868344, 28211982). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 254648). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 49 of the PPP1CB protein (p.Pro49Arg).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000490622	SCV001190249	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2019-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001265940	SCV001444112	pathogenic	Inborn genetic diseases	2016-07-06	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000257986	SCV001447547	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000257986	SCV001962241	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	PPP1CB: PS2, PM2, PS4:Moderate, PP2, PP4
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000490622	SCV001976798	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2021-10-05	criteria provided, single submitter	clinical testing	PM2, PP2, PP3, PP5
3billion	RCV000490622	SCV002011951	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 27264673, 28211982 and 27681385, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000490622	SCV002557913	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like disorder with loose anagen hair 2 (MIM#617506) (PMID: 30348783). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent variant reported in multiple individuals with Noonan syndrome-like disorder with loose anagen hair 2 (MIM#617506) (ClinVar, DECIPHER, PMID: 33491856). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002274002	SCV002559115	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University	RCV000490622	SCV002574761	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2022-09-08	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000490622	SCV004046312	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2		criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo heterozygous variant in multiple unrelated individuals with Noonan-like syndrome with loose anagen hair (PMID: 27264673, 27681385, 27868344, 28211982, 31474318). It is absent from the gnomAD population database and thus is presumed to be rare. The c.146C>G (p.Pro49Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.146C>G (p.Pro49Arg) variant is classified as Pathogenic.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000490622	SCV005367958	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2024-07-09	criteria provided, single submitter	clinical testing
OMIM	RCV000490622	SCV000579309	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2017-05-31	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001251211	SCV001426696	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000490622	SCV001428110	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2019-01-01	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257999	SCV001434812	likely pathogenic	Dandy-Walker syndrome		no assertion criteria provided	research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000490622	SCV001438015	likely pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2018-06-29	no assertion criteria provided	research
Coyote Medical Laboratory (Beijing), Coyote	RCV000490622	SCV001441279	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2018-05-28	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000257986	SCV001744847	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000257986	SCV001798142	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000257986	SCV001956324	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000257986	SCV001971001	pathogenic	not provided		no assertion criteria provided	clinical testing