rs121918470

Positions:

• chr12-112489105-A-C
• chr12-112489105-A-G
• chr12-112489105-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_Moderate PS2 PM2 PS4_Supporting PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.1529A>C (p.Gln510Pro) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). The p.Gln510Pro variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 4 family members (PP1_Moderate; APHP-Robert Debré Hospital: GTR Lab ID: 28338). The variant has also been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in PTPN11, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1_Moderate, PM2, PP2, PP3, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA256758/MONDO:0007893/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 8.95

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]

PTPN11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1529A>C	p.Gln510Pro	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1541A>C	p.Gln514Pro	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1526A>C	p.Gln509Pro	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1538A>C	p.Gln513Pro	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1529A>C	p.Gln510Pro	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1541A>C	p.Gln514Pro	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.542A>C	p.Gln181Pro	missense_variant	5/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2022	Published functional studies demonstrate a damaging effect in which Q510P leads to negligible catalytic activity and has a dominant positive effect on AKT activation (Hanna et al., 2006; Edouard et al., 2010); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 15690106, 20578946, 15520399, 16638574, 20308328, 24803665, 30896080, 31560489) -
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	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Sep 30, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 22, 2018	PTPN11:c.1529A>C; p.Gln510Pro is a well-known variant shown to co-segregate with disease in multiple families with LEOPARD syndrome (LS) (Kalidas 2005, Keren 2004), and has been identified in mixed cohorts of LS and Noonan syndrome (NS) patients (Tartaglia 2006 and Brasil 2010). This variant was shown to occur de novo in a four year old child with features of NS, although the age of the patient may have precluded a more accurate diagnosis of LS (Brasil 2010). Like other PTPN11 variants associated with LS, p.Gln510Pro has been shown to have a negative effect on PTP activity in cell culture, whereas variants associated with NS have a positive effect (Hanna 2006 and Edouard 2010). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database) but has been report to ClinVar as pathogenic by an expert panel (Variation ID: 13344). Based on these observations the p.Gln510Pro variant has been classified as pathogenic. -

LEOPARD syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013344 / PMID: 15520399 / 3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 15520399, 20578946). Different missense changes at the same codon (p.Gln510Arg, p.Gln510Glu, p.Gln510His, p.Gln510Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013345, VCV000040566, VCV000040567, VCV000811634, VCV000981537 / PMID: 15889278, 15948193, 21910226, 27193571 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Apr 03, 2017

The c.1529A>C (p.Gln510Pro) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). The p.Gln510Pro variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 4 family members (PP1_Moderate; APHP-Robert Debré Hospital: GTR Lab ID: 28338). The variant has also been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in PTPN11, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1_Moderate, PM2, PP2, PP3, PS4_Supporting. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jul 13, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Jul 19, 2022

- -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The PTPN11 c.1529A>C variant is predicted to result in the amino acid substitution p.Gln510Pro. This variant has been reported in multiple unrelated individuals with Noonan syndrome with or without multiple lentigines and arose de novo in at least one individual (Table 1, Keren et al. 2004. PubMed ID: 15520399; Table 2, Tartaglia et al. 2005. PubMed ID: 16358218; Brasil et al. 2010. PubMed ID: 20578946; Table 3, Chinton et al. 2019. PubMed ID: 31560489; Figure 3, Yu et al. 2019. PubMed ID: 30896080). This variant has been reported to segregate with Noonan syndrome with multiple lentigines in 5 individuals from 2 families (Table 1, Keren et al. 2004. PubMed ID: 15520399; Kalidas et al. 2004. PubMed ID: 15690106). In vitro experimental studies suggest this variant impacts protein function (Figure 3D, Edouard et al. 2010. PubMed ID: 20308328). Alternate nucleotide changes affecting the same amino acid (p.Gln510Glu, p.Gln510Arg, p.Gln510His), have been reported as pathogenic in individuals with PTPN11-associated disease (Bertola et al. 2005. PubMed ID: 15948193; Table 2, Tartaglia et al. 2005. PubMed ID: 16358218; Digilio et al. 2006. PubMed ID: 16733669; Wakabayashi et al. 2011. PubMed ID: 21910226; Table 3, Chinton et al. 2019. PubMed ID: 31560489). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, the ClinGen RASopathy expert panel interprets this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/13344/). Taken together, we interpret this variant as pathogenic. -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 28, 2014

The p.Gln510Pro variant in PTPN11 has been reported in at least 10 individuals w ith clinical features of LEOPARD syndrome and Noonan syndrome (Tartaglia 2006, K alidas 2005, Keren 2004, LMM upublished data) and segregated with disease in 3 a ffected relatives from 2 families (Kalidas 2005, Keren 2004). It has not been id entified in large population studies. Studies have shown that the Gln510Pro vari ant impacts protein function by decreasing the phosphatase activity of the prote in (Hanna 2006). In addition, a second variant at this codon (Gln510Glu) has be en identified more than 10 affected individuals and occurred de novo in at least one individual, suggesting that changes to this residue are not tolerated. In summary, this variant meets our criteria to be classified as pathogenic for Noon an spectrum disorders in an autosomal dominant manner. -

Noonan syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 28, 2019

Variant summary: PTPN11 c.1529A>C (p.Gln510Pro) results in a non-conservative amino acid change located in the protein-tyrosine phosphatase catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.1529A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Keren_2004, Kalidas_2005, Brasil_2010, Quaio_2012). These data indicate that the variant is very likely to be associated with disease. At least two publications reported experimental evidence demonstrating an impact on protein function (Hanna_2006, Edouard_2010). Five other submitters, including one expert panel (ClinGen RASopathy Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln510 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21677813, 22058153, 25708222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16638574, 20308328). 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. ClinVar contains an entry for this variant (Variation ID: 13344). This missense change has been observed in individual(s) with Noonan syndrome and/or Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) (PMID: 15520399, 15690106, 16358218, 20578946). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 510 of the PTPN11 protein (p.Gln510Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	5.1	.;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	D;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.97		Loss of MoRF binding (P = 0.0596);.;.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121918470; hg19: chr12-112926909;