VCV000013333.92 - ClinVar

NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)

Germline

Top reviewed classifications are shown here.

Submission summary:

49 submissions

45 submitters

12 conditions

Reviewed by expert panel

Pathogenic

Sep 2024 by ClinGen RASopa… FDA Recognized Database

for Noonan syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)

Variation ID: 13333 Accession: VCV000013333.92

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.13 12: 112450368 (GRCh38) [ NCBI UCSC ] 12: 112888172 (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	Apr 4, 2013	Oct 26, 2024	Sep 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.188A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002825.3:p.Tyr63Cys	missense
NM_001330437.1:c.188A>G
NM_001330437.2:c.188A>G	NP_001317366.1:p.Tyr63Cys	missense
NM_001374625.1:c.185A>G	NP_001361554.1:p.Tyr62Cys	missense
NM_080601.3:c.188A>G	NP_542168.1:p.Tyr63Cys	missense
NC_000012.12:g.112450368A>G
NC_000012.11:g.112888172A>G
NG_007459.1:g.36637A>G
LRG_614:g.36637A>G
LRG_614t1:c.188A>G
	Q06124:p.Tyr63Cys

... more HGVS ... less HGVS

Protein change

Y63C, Y62C

Other names

NM_002834.4(PTPN11):c.188A>G
NM_002834.5(PTPN11):c.188A>G

Canonical SPDI

NC_000012.12:112450367:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA220146 UniProtKB: Q06124#VAR_015606 OMIM: 176876.0008 dbSNP: rs121918459 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.
PTPN11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	972	984

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.
Noonan syndrome 1	Conflicting interpretations of pathogenicity (17)	criteria provided, conflicting classifications	Aug 29, 2024	RCV000014261.51
not provided	Pathogenic (15)	criteria provided, multiple submitters, no conflicts	Aug 21, 2023	RCV000077857.59
Noonan syndrome 3	Pathogenic (1)	criteria provided, single submitter	May 2, 2016	RCV000588678.9
Noonan syndrome	Pathogenic (3)	reviewed by expert panel	Sep 17, 2024	RCV000157000.24
LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1	Pathogenic (1)	criteria provided, single submitter	Dec 10, 2018	RCV001249667.12
RASopathy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000033468.26
B lymphoblastic leukemia lymphoma, no ICD-O subtype Lymphoma	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2017	RCV000722014.10
Juvenile myelomonocytic leukemia LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 25, 2022	RCV000515408.12
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 14, 2020	RCV001813198.11
Metachondromatosis	Pathogenic (1)	criteria provided, single submitter	Feb 14, 2021	RCV003147286.8
LEOPARD syndrome 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 6, 2022	RCV003137518.8
PTPN11-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV004528109.2
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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 (ClinGen RASopathy ACMG Specifications PTPN11 V2.1.0) Method: curation	Noonan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616372.4 First in ClinVar: Dec 19, 2017 Last updated: Oct 13, 2024	Publications: PubMed (6) PubMed: 12634870‚ 22711529‚ 16498234‚ 11704759‚ 24219368‚ 12325025 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/579af108-04e2-4cf7-9a40-35cbaa82b116 Comment: The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to … (more) The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; PMID: 16498234, 12634870, 12325025, 11704759). In-vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024). (less)
Pathogenic (Jan 07, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Noonan syndrome Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207167.3 First in ClinVar: Feb 06, 2015 Last updated: Apr 09, 2018	Publications: PubMed (9) PubMed: 11704759‚ 11992261‚ 14644997‚ 16498234‚ 12325025‚ 12634870‚ 12161469‚ 21407260‚ 22420426 Number of individuals with the variant: 2
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611303.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Pathogenic (Jun 15, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614839.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (33) PubMed: 26817465‚ 24451042‚ 26084119‚ 22465605‚ 25337068‚ 27104176‚ 23624134‚ 19077116‚ 26456833‚ 24037001‚ 23771920‚ 26495027‚ 25862627‚ 26607044‚ 27038324‚ 24458522‚ 15001945‚ 11704759‚ 22420426‚ 12325025‚ 12634870‚ 11992261‚ 16498234‚ 14644997‚ 17497712‚ 12161469‚ 22711529‚ 12960218‚ 24219368‚ 26242988‚ 24803665‚ 25156961‚ 21407260
Pathogenic (Mar 28, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000746635.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Number of individuals with the variant: 1 Clinical Features: Vascular skin abnormality (present) , Patent ductus arteriosus (present) , Osteopenia (present) , Narrow forehead (present) , Myalgia (present) , Muscle weakness (present) , Menorrhagia … (more) Vascular skin abnormality (present) , Patent ductus arteriosus (present) , Osteopenia (present) , Narrow forehead (present) , Myalgia (present) , Muscle weakness (present) , Menorrhagia (present) , Lumbar scoliosis (present) , Long toe (present) , Long face (present) , Joint laxity (present) , High, narrow palate (present) , Fatigue (present) , Dyspnea (present) , Delayed puberty (present) , Cupped ear (present) , Capillary hemangiomas (present) , Bruising susceptibility (present) , Bilateral ptosis (present) , Atrioventricular canal defect (present) , Absent patellar reflexes (present) , Abnormality of skeletal maturation (present) , Abnormality of bone mineral density (present) (less) Age: 30-39 years Sex: female Ethnicity/Population group: White Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2017-03-28 Testing laboratory interpretation: Pathogenic
Pathogenic (Apr 26, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	B lymphoblastic leukemia lymphoma, no ICD-O subtype Lymphoma Affected status: yes Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV000853187.1 First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018	Comment: This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine … (more) This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3. (less) Sex: female
Pathogenic (Apr 20, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Noonan syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061294.6 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (10) PubMed: 11992261‚ 15928039‚ 14644997‚ 16498234‚ 12325025‚ 17497712‚ 12634870‚ 12161469‚ 21407260‚ 22420426 Comment: The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with … (more) The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong. (less) Number of individuals with the variant: 52
Pathogenic (-)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: case-control	Noonan syndrome 1 Affected status: yes Allele origin: de novo	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital Accession: SCV000992395.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020	Number of individuals with the variant: 1 Clinical Features: hearing loss (present) , CafÃ© au lait macules (present) , Postnatal growth retardation (present) , Ocular hypertelorism (present) Family history: yes
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: unknown	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn Accession: SCV000999303.1 First in ClinVar: Dec 01, 2019 Last updated: Dec 01, 2019	Number of individuals with the variant: 1 Clinical Features: Hypertelorism (present) , Epicanthus (present) , Cryptorchidism (present) , Bruising susceptibility (present) , Abnormality of the thorax (present) , Pulmonic stenosis (present) , Ptosis (present)
Pathogenic (May 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001190264.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020
Pathogenic (Dec 10, 2018)	criteria provided, single submitter (ClinGen's RASopathy Expert Panel Consensus Methods for Variant Interpretation) Method: clinical testing	Noonan syndrome 1 LEOPARD syndrome 1 Metachondromatosis Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423672.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Comment: [ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], … (more) [ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. (less)
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976777.1 First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020	Publications: PubMed (1) PubMed: 34008892 Comment: PS3, PM1, PM2, PP2, PP3, PP5
Pathogenic (Jul 12, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059442.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Aug 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581037.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4, PP1_STR, PM1, PP2, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768758.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 11704759‚ 11992261‚ 12325025‚ 12634870‚ 20301303‚ 21533187‚ 22711529‚ 24935154 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER). (SP) 0801 - The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome (ClinVar, DECIPHER, PMIDs: 11704759; 12325025; 12634870). (SP) 0901 - The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro studies showed that the variant resulted in a gain of protein function (PMID: 22711529). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LEOPARD syndrome 1 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807148.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Telecanthus (present) , Joint laxity (present) , Abnormal nasal morphology (present) , Cryptorchidism (present) , Round ear (present) , Clinodactyly of the 5th finger (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Feb 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LEOPARD syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836226.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Feb 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000854621.2 First in ClinVar: May 29, 2016 Last updated: Mar 11, 2023
Pathogenic (Feb 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachondromatosis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835598.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	RASopathy Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004034113.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PTPN11-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046310.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that … (more) This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic. (less)
Uncertain significance (Feb 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004176586.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental … (more) The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (Jun 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226875.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PP1_strong, PP2, PP3, PM1, PS3_moderate Number of individuals with the variant: 8
Pathogenic (Mar 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826749.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253879.13 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 11704759‚ 11992261‚ 12325025‚ 12960218‚ 16498234‚ 21407260‚ 22711529 Comment: This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein … (more) This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884430.3 First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024	Comment: The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri … (more) The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218 (less)
Pathogenic (Aug 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382133.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PS1, PS3, PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state Clinical Features: Infantile muscular hypotonia (present) , Respiratory insufficiency due to muscle weakness (present) , Infantile onset (present) , Abnormal heart morphology (present) , Ventricular septal defect … (more) Infantile muscular hypotonia (present) , Respiratory insufficiency due to muscle weakness (present) , Infantile onset (present) , Abnormal heart morphology (present) , Ventricular septal defect (present) , Renal insufficiency (present) , Hypocalcemia (present) (less)
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000265840.1 First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015	Publications: PubMed (4) PubMed: 11704759‚ 11992261‚ 12161469‚ 22711529 Observation 1: Number of individuals with the variant: 1 Clinical Features: Facial features resembling Noonan Syndrome (present) , Bitemporal narrowing (present) , Pulmonic stenosis (present) , Cryptorchidism (present) Age: 0-9 years Sex: male Observation 2: Number of individuals with the variant: 1 Clinical Features: Congenital stenosis of pulmonary valve (present) , Congenital pulmonary insufficiency (present) , Paroxysmal superventricular tachcardia (present) Age: 0-9 years Sex: female
Pathogenic (May 02, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Noonan syndrome 3 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698066.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (3) PubMed: 12960218‚ 16498234‚ 12325025 Comment: Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for … (more) Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic. (less)
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782248.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016
Pathogenic (Mar 01, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000058290.9 First in ClinVar: Apr 04, 2013 Last updated: Dec 06, 2016	Publications: PubMed (2) PubMed: 11704759‚ 21407260 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 Number of individuals with the variant: 4 Sex: mixed
Pathogenic (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905629.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Clinical Features: Epicanthus (present) , Hypertelorism (present) , Low-set ears (present) , Failure to thrive (present) , Abnormal cardiac septum morphology (present) , Short stature (present) , … (more) Epicanthus (present) , Hypertelorism (present) , Low-set ears (present) , Failure to thrive (present) , Abnormal cardiac septum morphology (present) , Short stature (present) , Decreased body weight (present) , Wide intermamillary distance (present) , Atrioventricular canal defect (present) (less) Sex: female
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755589.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Indication for testing: Multiple Congenital Anomalies
Pathogenic (Jan 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV001984986.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: PS3, PS4, PM6, PP1, PP3, PP5
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: maternal	3billion Accession: SCV002012314.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021	Publications: PubMed (2) PubMed: 11992261‚ 26242988 Comment: Same nucleotide change resulting in same amino acid change has been previously observed in at least four similarly affected unrelated individuals (3billion dataset, ClinVar ID: … (more) Same nucleotide change resulting in same amino acid change has been previously observed in at least four similarly affected unrelated individuals (3billion dataset, ClinVar ID: VCV000372674.2, PMID: 11992261, 26242988, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001195). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Polyhydramnios (present) , Failure to thrive (present) , Pleural effusion (present) , Generalized edema (present) , Coarctation of aorta (present) , Proteinuria (present) , Abnormality … (more) Polyhydramnios (present) , Failure to thrive (present) , Pleural effusion (present) , Generalized edema (present) , Coarctation of aorta (present) , Proteinuria (present) , Abnormality of the coagulation cascade (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Patent ductus arteriosus (present) , Non-immune hydrops fetalis (present) , Premature birth (present) (less)
Pathogenic (Sep 14, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060861.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501823.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (16) PubMed: 11704759‚ 32164556‚ 30417923‚ 31560489‚ 24219368‚ 21407260‚ 26242988‚ 24803665‚ 29907801‚ 30055033‚ 31219622‚ 22711529‚ 32371413‚ 25156961‚ 32901917‚ 30692697 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Aug 11, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000057373.14 First in ClinVar: Jul 03, 2013 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its … (more) Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581) (less)
Pathogenic (Jan 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 LEOPARD syndrome 1 Metachondromatosis Juvenile myelomonocytic leukemia Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV002495907.2 First in ClinVar: Apr 11, 2022 Last updated: May 06, 2023	Comment: This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease … (more) This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic. (less)
Pathogenic (Aug 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197295.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jan 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246728.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PTPN11: PP1:Strong, PM1, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting Number of individuals with the variant: 4
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196657.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Publications: PubMed (1) PubMed: 11704759 Comment: Variant classified using ACMG guidelines
Pathogenic (Jan 15, 2015)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV000207652.1 First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015
Pathogenic (Jun 01, 2007)	no assertion criteria provided Method: literature only	NOONAN SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034509.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2019	Publications: PubMed (4) PubMed: 12325025‚ 11704759‚ 12161469‚ 17497712 Comment on evidence: In 2 unrelated families, Maheshwari et al. (2002) found that probands with Noonan syndrome (NS1; 163950) had a tyr63-to-cys (Y63C) mutation in exon 3. This … (more) In 2 unrelated families, Maheshwari et al. (2002) found that probands with Noonan syndrome (NS1; 163950) had a tyr63-to-cys (Y63C) mutation in exon 3. This same mutation was identified by Tartaglia et al. (2001). This mutation was also identified by Kosaki et al. (2002) in 2 patients. See 176876.0004 and Becker et al. (2007). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931284.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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: SCV001956732.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: research	Noonan syndrome 1 Affected status: yes Allele origin: unknown	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV003840159.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Number of individuals with the variant: 1
Pathogenic (Jul 04, 2024)	no assertion criteria provided Method: clinical testing	PTPN11-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004103329.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan … (more) The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101114.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
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Comment:

The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; PMID: 16498234, 12634870, 12325025, 11704759). In-vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024).

Comment:

The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong.

Comment:

[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER). (SP) 0801 - The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome (ClinVar, DECIPHER, PMIDs: 11704759; 12325025; 12634870). (SP) 0901 - The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro studies showed that the variant resulted in a gain of protein function (PMID: 22711529). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic.

Comment:

The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.

Comment:

The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218

Comment:

Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.

Comment:

Same nucleotide change resulting in same amino acid change has been previously observed in at least four similarly affected unrelated individuals (3billion dataset, ClinVar ID: VCV000372674.2, PMID: 11992261, 26242988, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001195). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581)

Comment:

This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic.

Comment:

The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Noonan Syndrome.	Adam MP	-	2022	PMID: 20301303
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE.	Seo GH	Clinical genetics	2020	PMID: 32901917
Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.	Miller CR	Cold Spring Harbor molecular case studies	2020	PMID: 32371413
Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations.	Athota JP	BMC medical genetics	2020	PMID: 32164556
Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina.	Chinton J	Archivos argentinos de pediatria	2019	PMID: 31560489
Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients.	Li X	Clinical genetics	2019	PMID: 31219622
Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.	Zhang J	Nature medicine	2019	PMID: 30692697
Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.	Bessis D	The British journal of dermatology	2019	PMID: 30417923
Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.	Leach NT	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29907801
Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.	Levin MD	American journal of medical genetics. Part A	2018	PMID: 30055033
Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome.	Jeong I	Annals of pediatric endocrinology & metabolism	2016	PMID: 27104176
Nutritional aspects of Noonan syndrome and Noonan-related disorders.	da Silva FM	American journal of medical genetics. Part A	2016	PMID: 27038324
Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations.	Atik T	Indian journal of pediatrics	2016	PMID: 26817465
New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations.	Čizmárová M	Annals of human genetics	2016	PMID: 26607044
The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome.	Joyce S	European journal of human genetics : EJHG	2016	PMID: 26242988
Nonsynonymous Single-Nucleotide Variations on Some Posttranslational Modifications of Human Proteins and the Association with Diseases.	Sun B	Computational and mathematical methods in medicine	2015	PMID: 26495027
Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia.	Mulero-Navarro S	Cell reports	2015	PMID: 26456833
The first PTPN1 1 mutations in hotspot exons reported in Moroccan children with Noonan syndrome and comparison of mutation rate to previous studies.	El Bouchikhi I	Turkish journal of medical sciences	2015	PMID: 26084119
External ear anomalies and hearing impairment in Noonan Syndrome.	van Trier DC	International journal of pediatric otorhinolaryngology	2015	PMID: 25862627
Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders.	Okamoto N	Clinical genetics	2015	PMID: 25156961
Clinical and Molecular Findings of Tunisian Patients with RASopathies.	Louati R	Molecular syndromology	2014	PMID: 25337068
Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations.	Yu ZH	Biochemistry	2014	PMID: 24935154
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.	Kiel C	Molecular systems biology	2014	PMID: 24803665
Behavioral profile in RASopathies.	Alfieri P	American journal of medical genetics. Part A	2014	PMID: 24458522
Diagnosis of Noonan syndrome and related disorders using target next generation sequencing.	Lepri FR	BMC medical genetics	2014	PMID: 24451042
MAPK activation in mature cataract associated with Noonan syndrome.	Hashida N	BMC ophthalmology	2013	PMID: 24219368
Tegumentary manifestations of Noonan and Noonan-related syndromes.	Quaio CR	Clinics (Sao Paulo, Brazil)	2013	PMID: 24037001
Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature.	Wang SR	The Journal of clinical endocrinology and metabolism	2013	PMID: 23771920
IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene.	Bertelloni S	Hormones (Athens, Greece)	2013	PMID: 23624134
Clinical and molecular analysis of RASopathies in a group of Turkish patients.	Şimşek-Kiper PÖ	Clinical genetics	2013	PMID: 22420426
Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome.	Martinelli S	The Journal of biological chemistry	2012	PMID: 22711529
Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy.	Ezquieta B	Revista espanola de cardiologia (English ed.)	2012	PMID: 22465605
Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.	Bowen ME	PLoS genetics	2011	PMID: 21533187
Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation.	Jongmans MC	European journal of human genetics : EJHG	2011	PMID: 21407260
Genotype differences in cognitive functioning in Noonan syndrome.	Pierpont EI	Genes, brain, and behavior	2009	PMID: 19077116
Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.	Becker K	American journal of medical genetics. Part A	2007	PMID: 17497712
A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population.	Takahashi I	The Tohoku journal of experimental medicine	2006	PMID: 16498234
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.	Kratz CP	Blood	2005	PMID: 15928039
Genotype-phenotype correlations in Noonan syndrome.	Zenker M	The Journal of pediatrics	2004	PMID: 15001945
Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.	Loh ML	Blood	2004	PMID: 14644997
Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes.	Sarkozy A	Journal of medical genetics	2003	PMID: 12960218
Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.	Musante L	European journal of human genetics : EJHG	2003	PMID: 12634870
PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.	Maheshwari M	Human mutation	2002	PMID: 12325025
PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.	Kosaki K	The Journal of clinical endocrinology and metabolism	2002	PMID: 12161469
PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.	Tartaglia M	American journal of human genetics	2002	PMID: 11992261
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.	Tartaglia M	Nature genetics	2001	PMID: 11704759
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/579af108-04e2-4cf7-9a40-35cbaa82b116	-	-	-	-
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Text-mined citations for rs121918459 ...

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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918459 ...