rs121918459

Positions:

• chr12-112450368-A-G
• chr12-112450368-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PP2 PP3 PM1 PS3 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220146/MONDO:0018997/004

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:48 U:1
• Conservation: PhyloP100: 9.31

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.188A>G	p.Tyr63Cys	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.188A>G	p.Tyr63Cys	missense_variant	3/16	1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251010 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460960 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726828

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000192 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:48 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 1 Pathogenic:16 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jul 12, 2018	- -
Pathogenic, criteria provided, single submitter	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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 -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Aug 29, 2024	ACMG Criteria: PS1, PS3, PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Jan 26, 2021	PS3, PS4, PM6, PP1, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS3, PM1, PM2, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -

not provided Pathogenic:15

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2023	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 -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	PTPN11: PP1:Strong, PM1, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2021	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2022	PP1_strong, PP2, PP3, PM1, PS3_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -

Noonan syndrome Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 07, 2015	- -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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. -

LEOPARD syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 06, 2022	ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2021	- -

PTPN11-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 04, 2024	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. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jan 25, 2022	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. -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 14, 2021

- -

Lymphoma;CN257934:B lymphoblastic leukemia lymphoma, no ICD-O subtype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Apr 26, 2017

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. -

Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Dec 10, 2018

[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]. -

Noonan syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 02, 2016

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. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.5	D;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.0030	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.93
MutPred		0.94		Loss of phosphorylation at Y63 (P = 0.048);Loss of phosphorylation at Y63 (P = 0.048);Loss of phosphorylation at Y63 (P = 0.048);Loss of phosphorylation at Y63 (P = 0.048);
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918459; hg19: chr12-112888172; COSMIC: COSV61007856; COSMIC: COSV61007856;