12-112489104-C-G

Position:

• chr12-112489104-C-G

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.1528C>G​(p.Gln510Glu) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Q510H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• 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]

PTPN11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a helix (size 16) in uniprot entity PTN11_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr12-112489106-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ 3.1293 (greater than the threshold 3.09). Trascript score misZ 4.9438 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 12-112489104-C-G is Pathogenic according to our data. Variant chr12-112489104-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 40566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489104-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1528C>G	p.Gln510Glu	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1540C>G	p.Gln514Glu	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1525C>G	p.Gln509Glu	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1537C>G	p.Gln513Glu	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1528C>G	p.Gln510Glu	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1540C>G	p.Gln514Glu	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.541C>G	p.Gln181Glu	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:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2023	Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); 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: 29696744, 30732632, 30384889, 35050212, 25708222, 21803945, 22058153, 21677813, 24935154, 19582499, 26742426, 15889278, 23673659, 16733669, 19273734, 16358218, 18241070, 28973083, 21910226, 20954246, 25724491, 25359717, 30050098, 29907801, 31219622, 31712860, 32164556, 31965297, 31370276, 32573669, 33318624) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -

Noonan syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Mar 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 27, 2018	A heterozygous missense variant, NM_002834.3(PTPN11):c.1528C>G, has been identified in exon 13 of 16 of the PTPN11 gene. The variant is predicted to result in a minor amino acid change from a glutamine to a glutamic acid at position 510 of the protein, NP_002825.3(PTPN11):p.(Gln510Glu). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the protein tyrosine phosphatase functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has previously been described multiple times as pathogenic in patients with Noonan syndrome and Noonan syndrome with multiple letigines with reported de novo cases (ClinVar). Additionally, functional analysis of cardiomyocyte cell lines demonstrated significant attenuation of myofibrillogenesis and increased proliferation, whilst mice overexpressing this variant showed increased cardiomyocyte size, heart-to-body weight ratios, interventricular septum thickness, cardiomyocyte disarray, thickened ventricular walls and depressed contractile function (Ishida, H., et al. (2011), Schramm, C., et al. (2012)). Three alternate variants in the same codon, p.(Gln510Arg), p.(Gln510Pro) and p.(Gln510His) have been reported multiple times in patients with Noonan syndrome and Noonan syndrome with multiple letigines (ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory in a 3-month-old male with cardiovascular disease (dysplastic pulmonary valve, severe pulmonic stenosis, thickened aortic valve leaflets, abnorma mitral valve, ventricular hypertrophy), microcephaly, failure to thrive, dysmorphisms (hypertelorism, down-slanting palpebral fissures, retrgnathia, low-set posteriorly rotated ears), left pelvic kidney -

RASopathy Pathogenic:2

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	Nov 27, 2023	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 510 of the PTPN11 protein (p.Gln510Glu). This variant is not present in population databases (gnomAD no frequency). 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: 15889278, 16733669, 19077116, 19582499, 20954246, 21677813, 22190897, 25708222). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40566). 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: 21803945, 22058153, 23673659, 24935154, 25708222, 26742426). 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: 2057894, 15520399, 15690106, 16358218). 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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 15, 2020

ACMG classification criteria: PS2, PS4, PM2, PP2, PP3 -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been reported in the literature in individuals affected with Noonan syndrome with multiple lentigines (NSML, also referred to as LEOPARD syndrome) or Noonan syndrome, also as a de novo alteration (PMID: 16733669, 22190897, 25708222, 21677813, 20954246, 15889278, 19582499, 19077116). In-vitro studies have shown that this missense change abolishes PTPN11 phosphatase activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222), and mouse models have demonstrated altered cardiac function (PMID: 22058153). The c.1528C>G (p.Gln510Glu) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1528C>G (p.Gln510Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants affecting the same amino acid residue, including a c.1530G>T (p.Gln510His), have been reported individuals with NSML or Noonan syndrome (PMID: 27193571, 21910226, 15520399, 16358218, 20578946, 15690106). 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.1528C>G (p.Gln510Glu) variant is classified as Pathogenic. -

Noonan syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 07, 2016

Variant summary: The c.1528C>G in a PTPN11 gene alters a highly conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant has been reported in multiple affected individuals with NSRD with early onset HCM. The variant is absent in control dataset of ExAC. Animal model studies concluded that cardiomyocyte-specific expression of Q510E-Shp2 was sufficient to induce the HCM phenotype. In addition, other variants affecting codon Q510 have been reported in pts with NSRD. Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified 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

Jun 14, 2012

The p.Gln510Glu variant in PTPN11 has been reported in >10 individuals with clin ical features of RASopathy disorders (Faienza 2009, Lehmann 2009, Tartaglia 2006 , Wakabayashi 2011, Digilio 2006, Ganigara 2011, Limongelli 2008, Takahashi 2005 , and LMM data). This variant has been reported to have occurred de novo in at l east one individual (Faienza 2009). Furthermore, animal models in mice have show n that this variant causes hypertrophic cardiomyopathy (Schramm 2012). In summar y, this variant meets criteria to be classified as pathogenic for RASopathy diso rder in an autosomal dominant manner. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2019

The p.Q510E pathogenic mutation (also known as c.1528C>G), located in coding exon 13 of the PTPN11 gene, results from a C to G substitution at nucleotide position 1528. The glutamine at codon 510 is replaced by glutamic acid, an amino acid with highly similar properties. This mutation has been reported in numerous individuals with Noonan syndrome or Noonan syndrome with multiple lentigines, at least two of which are likely of de novo origin (Takahashi K et al. Eur. J. Pediatr. 2005;164:497-500; Digilio MC et al. Eur. J. Pediatr. 2006;165:803-5; Faienza MF et al. Pediatr Cardiol. 2009;30:1012-5; Ganigara M et al. Ann Pediatr Cardiol. 2011;4:74-6; Hahn A et al. Am. J. Med. Genet. A. 2015;167A:744-51; Sayeed M et al. Int J clin Cardiol. 2015;2:052-6; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29). In addition, assays in both in vitro and in vivo models have demonstrated disrupted PTPN11 protein function for p.Q510E, and resultant hypertrophic cardiomyopathy (Ishida H et al. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1531-9; Schramm C et al. Am. J. Physiol. Heart Circ. Physiol. 2012;302:H231-43; Yu ZH et al. Biochemistry. 2014;53:4136-51; Noda S et al. Biochem. Biophys. Res. Commun. 2016;469:1133-9). Based on the supporting evidence, p.Q510E 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	0.94
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	.;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.98		Loss of MoRF binding (P = 0.0392);.;.;
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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: rs397507549; hg19: chr12-112926908; COSMIC: COSV61007076; COSMIC: COSV61007076;