rs397507548

Positions:

• chr12-112489093-A-C
• chr12-112489093-A-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1517A>C​(p.Gln506Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q506R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 55799
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-112489093-A-C is Pathogenic according to our data. Variant chr12-112489093-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 40563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489093-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1517A>C	p.Gln506Pro	missense_variant	13/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1529A>C	p.Gln510Pro	missense_variant	13/16
PTPN11	NM_001374625.1	c.1514A>C	p.Gln505Pro	missense_variant	13/16
PTPN11	XM_011538613.3	c.1526A>C	p.Gln509Pro	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1517A>C	p.Gln506Pro	missense_variant	13/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 02, 2018	- -
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	GeneDx	Jun 06, 2022	Published functional studies demonstrate p.(Q506P) affects the catalytic phosphatase domain (PTP) of the protein and interferes with its normal phosphatase activity (Qiu et al., 2014; Yu et. al, 2014); The majority of missense variants in this gene are considered pathogenic (HGMD); Located in the critical PTP functional domain and mutational hotspot region (Yu et al. 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15121796, 15928039, 16358218, 22528600, 24628801, 14961557, 30508783, 32164556, 14644997, 15987685, 26742426, 24803665, 18470943, 15723289, 20954246, 20301557, 30732632, 31219622, 33240318, 24935154) -

PTPN11-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 08, 2024	The PTPN11 c.1517A>C variant is predicted to result in the amino acid substitution p.Gln506Pro. This variant has been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (see for example - Conti et al. 2003. PubMed ID: 14961557; Athota et al. 2020. PubMed ID: 32164556) and in several of the individuals it was found to be de novo (see for example - Chen et al. 2019. PubMed ID: 30732632). Functional and structural studies found this variant inhibits catalytic activity (Keilhack et al. 2005. PubMed ID: 15987685; Qiu et al. 2014. PubMed ID: 24628801; Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Oct 28, 2020	This variant has been previously reported in several individuals with PTPN11-related disorders (PMID: 14961557, 15928039, 22528600, 30732632, 31219622, 32164556), and it was a de novo change in at least three patients (PMID: 30732632). In-vitro functional assessment of this alteration revealed that it affects the normal phosphatase activity of the protein (PMID: 15987685, 24935154, 24628801). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1529A>C (p.Gln510Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1529A>C (p.Gln510Pro) variant is classified as Pathogenic. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 506 of the PTPN11 protein (p.Gln506Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome or Noonan syndrome with multiple lentigines, some of whom also had a myeloproliferative disorder (PMID: 14961557, 15723289, 15928039, 18470943, 20954246, 22528600). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40563). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 24935154, 26742426). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2020	Variant summary: PTPN11 c.1517A>C (p.Gln506Pro) 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.1517A>C has been reported in the literature in individuals affected with Noonan Syndrome including de novo occurrences (Kratz_2005, Willig_2015, Li_2019, Athota_2020). These data indicate that the variant is likely to be associated with disease. Functional studies report this variant exhibits reduced catalytic activity (Yu_2014, Qiu_2014). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2015

proposed classification - variant undergoing re-assessment, contact laboratory -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 09, 2022

The c.1517A>C is a known pathogenic variant that has been reported in multiple unrelated individuals with Noonan spectrum disorders [PMID: 14961557, 15121796,15928039, 15723289, 20954246, 22528600]. This variant is reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID:40563). The c.1517A>C variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1517A>C variant is located in exon 13 of this 16-exon gene and is predicted to replace an evolutionarily conserved glutamine amino acid with proline at position 506 in the protein-tyrosine phosphatase domain of the encoded protein [PMID: 24628801]. In silico predictions are in favor of damaging effect for p.(Gln506Pro) variant [(CADD v1.6 = 32, REVEL = 0.9)]. Published functional studies have shown reduced catalytic phosphatase activity of protein carrying the p.(Gln506Pro) variant [PMID: 15987685, 24628801, 24935154, 26742426]. Based on available evidence this de novo c.1517A>C p.(Gln506Pro) variant identified in PTPN11 is classified as Pathogenic. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987685; 24935154; 26742426) - PS3.The c.1517A>C;p.(Gln506Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40563; PMID: 18470943; PMID: 14961557; PMID: 15723289; PMID: 15928039; PMID: 20954246; PMID: 22528600) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Y_phosphatase) - PM1. This variant is not present in population databases (rs397507548- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2016

The p.Q506P pathogenic mutation (also known as c.1517A>C), located in coding exon 13 of the PTPN11 gene, results from an A to C substitution at nucleotide position 1517. The glutamine at codon 506 is replaced by proline, an amino acid with similar properties. This mutation was first described as a de novo occurrence, paternity not confirmed, in a patient with a clinical diagnosis of Noonan syndrome with multiple lentigines (NSML, referred to as LEOPARD syndrome) including findings of mild hypertelorism, pulmonic stenosis, unilateral sensorineural hearing loss, and mild cognitive impairment (Conti E et al. Hum. Mutat., 2003 Jun;21:654). It has subsequently been reported in additional patients with Noonan syndrome or NSML (Derbent M et al. Am. J. Med. Genet. A, 2010 Nov;152A:2768-74; Piard J et al. Am. J. Med. Genet. A, 2012 Jun;158A:1406-10). Structural and functional studies indicate that this mutation results in a weakened auto-inhibited enzyme conformation leading to prolonged substrate turnover, producing a gain-of-function rasopathy phenotype through sustained activation of the RAS-ERK pathway (Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

LEOPARD syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.87	P;.;.
Vest4		0.98
MutPred		0.98		Loss of MoRF binding (P = 0.057);.;.;
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: rs397507548; hg19: chr12-112926897; COSMIC: COSV61007665; COSMIC: COSV61007665;