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)
ClinVar Genomic variation as it relates to human health
NM_002709.3(PPP1CB):c.146C>G (p.Pro49Arg)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
for
RASopathy
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002709.3(PPP1CB):c.146C>G (p.Pro49Arg)
Variation ID: 254648 Accession: VCV000254648.60
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p23.2 2: 28776944 (GRCh38) [ NCBI UCSC ] 2: 28999810 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 23, 2016 Oct 20, 2024 Sep 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002709.3:c.146C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002700.1:p.Pro49Arg missense NM_206876.2:c.146C>G NP_996759.1:p.Pro49Arg missense NC_000002.12:g.28776944C>G NC_000002.11:g.28999810C>G NG_052878.1:g.30197C>G P62140:p.Pro49Arg - Protein change
- P49R
- Other names
-
NM_002709.3(PPP1CB):c.146C>G
- Canonical SPDI
- NC_000002.12:28776943:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PPP1CB | - | - |
GRCh38 GRCh37 |
251 | 280 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2023 | RCV000257986.42 | |
| Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Jul 9, 2024 | RCV000490622.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 6, 2016 | RCV001265940.3 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001251211.3 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001257999.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002274002.3 | |
| Pathogenic (1) |
reviewed by expert panel
|
Sep 17, 2024 | RCV004732471.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 17, 2024)
|
reviewed by expert panel
Method: curation
|
RASopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV005367861.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Nov 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000928041.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Noonan Syndrome Panel
|
|
|
|
Pathogenic
(May 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001190249.1
First in ClinVar: Jun 04, 2017 Last updated: Jun 04, 2017 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447547.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Low-set ears (present) , Failure to thrive (present) , Macrocephaly (present) , Optic atrophy (present) , Abnormality of hair growth rate (present) , Hypertelorism (present) … (more)
Low-set ears (present) , Failure to thrive (present) , Macrocephaly (present) , Optic atrophy (present) , Abnormality of hair growth rate (present) , Hypertelorism (present) , Cardiomyopathy (present) , Motor delay (present) , Nystagmus (present) , Strabismus (present) (less)
Sex: female
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002011951.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormal facial shape (present) , Craniosynostosis syndrome (present) , Autistic behavior (present) , Cryptorchidism (present) , Hypertelorism (present) , Wide nasal bridge (present) , Delayed … (more)
Abnormal facial shape (present) , Craniosynostosis syndrome (present) , Autistic behavior (present) , Cryptorchidism (present) , Hypertelorism (present) , Wide nasal bridge (present) , Delayed speech and language development (present) , Cryptorchidism (present) , Isolated scaphocephaly (present) , Short neck (present) , Generalized hypotonia (present) , Macrocephaly (present) , Delayed gross motor development (present) (less)
|
|
|
Pathogenic
(Sep 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University
Accession: SCV002574761.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Clinical Features:
Prominent forehead (present) , Low-set ears (present) , Short stature (present)
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Jul 06, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444112.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Neurodevelopmental delay (present) , Atrial septal defect (present) , Pulmonic stenosis (disease) (present) , Heart murmur (present) , Abnormality of brain morphology (present) , Failure … (more)
Neurodevelopmental delay (present) , Atrial septal defect (present) , Pulmonic stenosis (disease) (present) , Heart murmur (present) , Abnormality of brain morphology (present) , Failure to thrive (present) , Gastroesophageal reflux (present) , Macrocephalus (present) , Short stature (present) , Plagiocephaly (present) , Wide anterior fontanel (present) , Prominent forehead (present) , Craniofacial asymmetry (present) , Midface retrusion (present) , Downslanted palpebral fissures (present) , Hypertelorism (present) , Telecanthus (present) , Low-set ears (present) , Posteriorly rotated ears (present) , Short nose (present) , Depressed nasal bridge (present) , Anteverted nares (present) , Thick lower lip vermilion (present) , Abnormality of the lip (present) , Retrognathia (present) , Micrognathia (present) , Short neck (present) , Sparse hair (present) , Hypoplastic nipples (present) , Broad thumb (present) , Single transverse palmar crease (present) , Abnormally lax or hyperextensible skin (present) , Esotropia (present) , Hyperhidrosis (present) , Nevus (present) , Hemangioma (present) , Recurrent otitis media (present) (less)
Sex: female
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Neurodevelopmental delay (present) , Failure to thrive (present) , Pulmonic stenosis (disease) (present) , Strabismus (present) , Hypermetropia (present) , Increased intraocular pressure (present) , … (more)
Neurodevelopmental delay (present) , Failure to thrive (present) , Pulmonic stenosis (disease) (present) , Strabismus (present) , Hypermetropia (present) , Increased intraocular pressure (present) , Sparse hair (present) , Hypertrichosis (present) , Hirsutism (present) , Dolichocephaly (present) , Narrow forehead (present) , Downslanted palpebral fissures (present) , Posteriorly rotated ears (present) , Thick eyebrow (present) , Gastroesophageal reflux (present) , Abnormality of the kidney (present) (less)
Sex: female
Ethnicity/Population group: African American/Scottish/Puerto Rican
|
|
|
Pathogenic
(Oct 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000299373.3
First in ClinVar: Oct 23, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 2
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046312.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
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, … (more)
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. (less)
|
|
|
Pathogenic
(Jan 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933113.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Jul 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV005367958.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
|
|
Pathogenic
(Apr 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962241.20
First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024 |
Comment:
PPP1CB: PS2, PM2, PS4:Moderate, PP2, PP4
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Aug 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
de novo
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000609586.1
First in ClinVar: Oct 23, 2016 Last updated: Oct 23, 2016 |
|
|
|
Pathogenic
(Jun 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000861880.1
First in ClinVar: Oct 23, 2016 Last updated: Oct 23, 2016 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Oct 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976798.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM2, PP2, PP3, PP5
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental delay
Affected status: yes
Allele origin:
de novo
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559115.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557913.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
|
|
|
Pathogenic
(May 31, 2017)
|
no assertion criteria provided
Method: literature only
|
NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000579309.1
First in ClinVar: Jun 04, 2017 Last updated: Jun 04, 2017 |
Comment on evidence:
In 3 unrelated patients with Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2; 617506), Gripp et al. (2016) identified heterozygosity for a de novo c.146C-G … (more)
In 3 unrelated patients with Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2; 617506), Gripp et al. (2016) identified heterozygosity for a de novo c.146C-G transversion (c.146C-G, NM_206876.1) in the PPP1CB gene, resulting in a pro49-to-arg (P49R) substitution at a highly conserved residue. The mutation was not found in the 1000 Genomes Project, NHLBI Exome Variant Server, ExAC, or dbSNP (build 137) databases. In 4 patients with developmental delay and/or intellectual disability, who also exhibited dysmorphic features including slow-growing hair, Ma et al. (2016) identified heterozygosity for the P49R mutation in the PPP1CB gene, located between alpha helices A and beta loop 1 within the catalytic core. In a 9-year-old boy who was diagnosed with Noonan syndrome and also had unusual hair, Zambrano et al. (2017) identified heterozygosity for the P49R mutation in the PPP1CB gene, which was shown to have arisen de novo. In a 12-year-old Brazilian boy with features of Noonan syndrome and hair abnormalities, Bertola et al. (2017) identified heterozygosity for the recurrent P49R mutation in PPP1CB. This patient also exhibited craniosynostosis involving the sagittal and bilateral partial coronal sutures. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Noonan syndrome
Affected status: yes
Allele origin:
de novo
|
Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001426696.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Dandy-Walker malformation
Affected status: yes
Allele origin:
de novo
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001434812.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
|
|
|
Likely pathogenic
(Jun 29, 2018)
|
no assertion criteria provided
Method: research
|
Noonan syndrome-like disorder with loose anagen hair 2
Affected status: yes
Allele origin:
de novo
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001438015.1
First in ClinVar: Apr 02, 2021 Last updated: Apr 02, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Robinow syndrome (present)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798142.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744847.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956324.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Jan 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 2
Affected status: yes
Allele origin:
de novo
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001428110.1
First in ClinVar: Aug 13, 2020 Last updated: Aug 13, 2020 |
|
|
|
Pathogenic
(May 28, 2018)
|
no assertion criteria provided
Method: clinical testing
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Noonan syndrome-like disorder with loose anagen hair 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Coyote Medical Laboratory (Beijing), Coyote
Accession: SCV001441279.1
First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Increased head circumference (present) , Hypertelorism (present) , Postnatal growth retardation (present) , Delayed gross motor development (present)
Family history: yes
Secondary finding: no
Method: exome sequencing with trio,and validation by sanger sequencing
Testing laboratory: Coyote Medical Laboratory (Beijing)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971001.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Comment:
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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).
Comment:
PPP1CB: PS2, PM2, PS4:Moderate, PP2, PP4
Comment:
PM2, PP2, PP3, PP5
Comment:
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
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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).
Comment:
PPP1CB: PS2, PM2, PS4:Moderate, PP2, PP4
Comment:
PM2, PP2, PP3, PP5
Comment:
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
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported. | Huckstadt V | American journal of medical genetics. Part A | 2021 | PMID: 33491856 |
| Redefining the Etiologic Landscape of Cerebellar Malformations. | Aldinger KA | American journal of human genetics | 2019 | PMID: 31474318 |
| SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. | Young LC | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 30348783 |
| The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype. | Bertola D | American journal of medical genetics. Part A | 2017 | PMID: 28211982 |
| Further evidence that variants in PPP1CB cause a rasopathy similar to Noonan syndrome with loose anagen hair. | Zambrano RM | American journal of medical genetics. Part A | 2017 | PMID: 27868344 |
| De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease. | Ma L | Human genetics | 2016 | PMID: 27681385 |
| A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. | Gripp KW | American journal of medical genetics. Part A | 2016 | PMID: 27264673 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PPP1CB | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7fa10769-861e-4c3c-b1b9-0dc138685921 | - | - | - | - |
| - | - | - | - | DOI: 10.1002/ajmg.a.62733 |
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Text-mined citations for rs886037952 ...
HelpThese citations are identified by LitVar using
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.