VCV000667025.20 - ClinVar

NM_002709.3(PPP1CB):c.201A>G (p.Gln67=)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Benign

for RASopathy

Classification is based on the expert panel submission

Dec 2024 by ClinGen RASopathy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002709.3(PPP1CB):c.201A>G (p.Gln67=)

Variation ID: 667025 Accession: VCV000667025.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.2 2: 28778825 (GRCh38) [ NCBI UCSC ] 2: 29001691 (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	Aug 26, 2019	Feb 23, 2026	Dec 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002709.3:c.201A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002700.1:p.Gln67=	synonymous
NM_002709.2:c.201A>G
NM_206876.2:c.201A>G	NP_996759.1:p.Gln67=	synonymous
NC_000002.12:g.28778825A>G
NC_000002.11:g.29001691A>G
NG_052878.1:g.32078A>G

... more HGVS ... less HGVS

Protein change

Other names

NM_002709.3(PPP1CB):c.201A>G
p.Gln67=

Canonical SPDI

NC_000002.12:28778824:A:G

Global minor allele frequency (GMAF) Help The 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.

0.49541 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.57257

1000 Genomes Project 0.49541

1000 Genomes Project 30x 0.50016

The Genome Aggregation Database (gnomAD), exomes 0.53212

Trans-Omics for Precision Medicine (TOPMed) 0.55263

Exome Aggregation Consortium (ExAC) 0.54468

The Genome Aggregation Database (gnomAD) 0.56723

The Genome Aggregation Database (gnomAD), exomes 0.57916

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.59506

Links

ClinGen: CA1589199 dbSNP: rs1128416 VarSome

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
Gene	OMIM	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		No evidence available	No evidence available	GRCh38 GRCh37	374	408

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.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Apr 4, 2023	RCV000825640.6
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 4, 2026	RCV001683665.9
Noonan syndrome-like disorder with loose anagen hair 2	Benign (1)	criteria provided, single submitter	Oct 25, 2021	RCV001789369.2
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 4, 2018	RCV002415953.2
RASopathy	Benign (1)	reviewed by expert panel	Dec 3, 2024	RCV005253651.1

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.	Expand all rows Collapse all rows 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.
Benign (Dec 03, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen RASopathy ACMG Specifications PPP1CB V1.3.0)	RASopathy (Autosomal dominant inheritance)	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV005903439.1 First in ClinVar: Apr 13, 2025 Last updated: Apr 13, 2025	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/92c34e06-f193-405c-a099-e2ab6cede4d0 Comment: show The c.201A>G (p.Gln67=) variant in PPP1CB is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, the computational predictor REVEL does not predict a damaging effect on PPP1CB function (BP4, BP7). The filtering allele frequency in gnomAD v2 is 60.64% in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.3; 12/3/2024) (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (Mar 12, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967010.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Comment: show p.Asp58Asp in exon 4 of p.Gln67Gln: This variant is not expected to have clinica l significance because it has been identified in 60.975% (77029/126328) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs1128416). ACMG/AMP Criteria applied: BA1. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 31

Benign (Oct 02, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001902907.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Oct 25, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Noonan syndrome-like disorder with loose anagen hair 2	Genome-Nilou Lab Accession: SCV002031811.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Benign (Apr 04, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003929299.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Dec 04, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002718478.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: show This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal dominant inheritance)	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005239882.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Benign (Apr 26, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007320395.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 117

Benign (Feb 04, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002332485.5 First in ClinVar: Apr 08, 2022 Last updated: Feb 23, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The c.201A>G (p.Gln67=) variant in PPP1CB is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, the computational predictor REVEL does not predict a damaging effect on PPP1CB function (BP4, BP7). The filtering allele frequency in gnomAD v2 is 60.64% in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.3; 12/3/2024)

Comment:

p.Asp58Asp in exon 4 of p.Gln67Gln: This variant is not expected to have clinica l significance because it has been identified in 60.975% (77029/126328) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs1128416). ACMG/AMP Criteria applied: BA1.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/92c34e06-f193-405c-a099-e2ab6cede4d0	-	-	-	-

Text-mined citations for rs1128416 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Mar 01, 2026