12-112489048-C-T

Position:

• chr12-112489048-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1472C>T​(p.Pro491Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P491A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.57

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 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112489048-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 12-112489048-C-T is Pathogenic according to our data. Variant chr12-112489048-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489048-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1472C>T	p.Pro491Leu	missense_variant	13/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1484C>T	p.Pro495Leu	missense_variant	13/16
PTPN11	NM_001374625.1	c.1469C>T	p.Pro490Leu	missense_variant	13/16
PTPN11	XM_011538613.3	c.1481C>T	p.Pro494Leu	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1472C>T	p.Pro491Leu	missense_variant	13/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 21407260, 29493581, 31219622, 28830562, 30050098, 29907801, 16358218, 16804314, 14982869, 18470943, 32737134, 23624134, 29625052, 15712196, 22781091, 20186801, 32059087, 15985475) -
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	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	- -

Noonan syndrome 1 Pathogenic:3

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	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss- 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 (PMID: 11992261, PMID: 24935154, PMID: 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tyrosine-protein phosphatase domain (Uniprot). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These alternative missense changes p.(Pro491Ala), p.(Pro491Ser), p.(Pro491Thr), p.(Pro491His) have been reported many times as pathogenic, and are observed in individuals with Noonan syndrome (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic. Affected individuals with this variant either inherited it from an affected parent, or the variant had arisen de novo (ClinVar, PMID: 22781091). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040552) and different missense changes at the same codon (p.Pro491Ala, p.Pro491His, p.Pro491Ser, p.Pro491Thr / ClinVar ID: VCV000040549, VCV000040550, VCV000040551, VCV000181503) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 24, 2019	The PTPN11 c.1472C>T; p.Pro491Leu variant (rs397507540) is reported in the literature in multiple individuals affected with Noonan syndrome (Aoki 2008, Ezquieta 2012, Jongmans 2011, Merks 2005, Pierpont 2010, Tartaglia 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40552), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 491 is highly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, other amino acid substitutions at this codon (Ser, His, Thr, Phe) have been reported in individuals with Noonan syndrome and are considered pathogenic (Aoki 2008, Ezquieta 2012, Jongmans 2011, Pierpont 2010, Tartaglia 2006). Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. Merks JH et al. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet A. 2005 Apr 15;134A(2):132-43. Pierpont EI et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010 Mar;152A(3):591-600. 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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Feb 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2018	The p.Pro491Leu variant in PTPN11 has been reported in >10 individuals with clin ical features of Noonan syndrome, including apparently de novo occurrences in 1 individual with Noonan syndrome and 1 individual with Noonan syndrome and non-Ho dgkin lymphoma (Binder 2005, Merks 2005, Chan 2006, Tartaglia 2006, Jongmans 201 1, Digilio 2012, Bertelloni 2013, LMM data, ClinVar Variation ID 40552). It also segregated in at least 3 affected relatives of two families (Binder 2005, Digil io 2012). Additionally, the p.Pro491Leu variant has been reported as a somatic c hange in individuals with acute lymphoblastic leukemia (ALL; Tartaglia 2004). Th is variant was absent from large population studies. Finally, several different variants at position 491 (p.Pro491Ala, p.Pro491Thr, p.Pro491His, p.Pro491Ser, an d p.Pro491Phe) have been identified in individuals with Noonan syndrome (LMM dat a, ClinVar), suggesting that changes at this position are not tolerated. In summ ary, this variant meets criteria to be classified as pathogenic for Noonan syndr ome in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PM5_Strong , PM2, PP1, PP2. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2021	Variant summary: PTPN11 c.1472C>T (p.Pro491Leu) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251480 control chromosomes. c.1472C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Binder_2005, Chan_2006, Diglio_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 491 of the PTPN11 protein (p.Pro491Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15985475, 18470943, 20186801, 22781091, 23624134). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40552). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16358218, 17020470, 19077116, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15985475, 21407260, 24803665] -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2023

The PTPN11 c.1472C>T variant is predicted to result in the amino acid substitution p.Pro491Leu. This variant has been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (See for example, Table 1, Binder et al. 2005. PubMed ID: 15985475; Table 1, Leoni et al. 2021. PubMed ID: 34643321; Table 2, Tartaglia et al. 2005. PubMed ID: 16358218). Other variants affecting the same amino acid, Pro491Ser and Pro491His, have been classified as pathogenic (Internal Data, PreventionGenetics). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.2	D;.;.
REVEL	Pathogenic	0.68
Sift	Benign	0.037	D;.;.
Sift4G	Benign	0.63	T;T;T
Polyphen		0.53	P;.;.
Vest4		0.90
MutPred		0.89		Gain of ubiquitination at K492 (P = 0.1008);.;.;
MVP		0.98
MPC		1.9
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397507540; hg19: chr12-112926852; COSMIC: COSV61004831; COSMIC: COSV61004831;