12-112450408-G-T

Position:

• chr12-112450408-G-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.228G>T​(p.Glu76Asp) variant causes a missense change involving the alteration of a non-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 Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76A) 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:12
• Conservation: PhyloP100: 3.04

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 21 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 8) in uniprot entity PTN11_HUMAN there are 16 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 chr12-112450407-A-C is described in Lovd as [Likely_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, 0.932
• PP5: Variant 12-112450408-G-T is Pathogenic according to our data. Variant chr12-112450408-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 40502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450408-G-T is described in Lovd as [Likely_pathogenic]. Variant chr12-112450408-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.228G>T	p.Glu76Asp	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.228G>T	p.Glu76Asp	missense_variant	3/16	1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	Reported previously in association with Noonan syndrome (Tartaglia et al., 2006; Musante et al., 2003); Published functional studies demonstrate a damaging effect; p.(E76D) results in abnormally increased activity levels of the PTPN11 protein (Tartaglia et al., 2006; Bocchinfuso et al., 2007); Missense variants in this gene are often 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: 12634870, 20308328, 17177198, 29907801, 30029678, 16830086, 30050098, 32676024, 16358218, 24077912, 27535533, 11992261, 9491886, 16053901, 29493581) -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2017	Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 122184 control chromosomes (ACMG PM2). This variant is found in the N-SH2 domain (IPR000980), a regulatory module of intracellular signaling cascades through its interaction with high affinity to phosphotyrosine-containing target peptides (ACMG PM1). This is a hotspot, with multiple missense variants in the same residue being known likely pathogenic variants (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly). In addition, multiple functional studies (Tartaglia_AJHG_2006, Edouard_MCB_2010, Keilhack_JBC_2005) showed that this variant increased basal and stimulated phosphatase activity by as much as 3-fold, determining a gain-of-function phenotype (ACMG PS3). This variant, and another variant c.228G>C that leads to the same amino acid change (E76D) have been reported in several patients with a clinical diagnosis of Noonan syndrome (ACMG PS1). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic (ACMG PP5). Lastly, these evidences support the classification of this variant as "Pathogenic" based upon ACMG guidelines (PS1, PS3, PM1, PM2, PP5). Taken together, this variant is classified as Pathogenic. -
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	Oct 04, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). ClinVar contains an entry for this variant (Variation ID: 40502). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506, 16358218, 17177198). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Apr 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2022	The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia 2006 PMID: 16358218, Power 2006 PMID: 16830086, Digilio 2011 PMID: 22190897, Zhu 2018 PMID: 30029678, Leach 2019 PMID: 29907801, LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 40502). It was absent from large population studies. Notably, a different nucleotide substitution at the same position (c.228G>C) resulting in the same amino acid change has been reported in >10 individuals with clinical features of Noonan syndrome (Tartaglia 2001 PMID: 11704759, Tartaglia 2006 PMID: 16358218, Edouard 2010 PMID: 20308328, LMM data). In addition, there are 4 other pathogenic amino acid substitutions at this position (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly); all these variants were also absent in large population studies. In vitro functional studies support an impact on protein function (Keilhack 2005 PMID: 15987685, Bocchinfuso 2007 PMID: 17177198, Edouard 2010 PMID: 20308328). Additionally, this variant lies in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (Gelb 2018 PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Strong, PS3_Supporting. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

-

- -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2024

The PTPN11 c.228G>T variant is predicted to result in the amino acid substitution p.Glu76Asp. This variant has been reported in many individuals with Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218; Table S3, Leach et al. 2019. PubMed ID: 29907801; Table S4, Zhu et al. 2018. PubMed ID: 30029678). Functional studies support this variants pathogenicity (Edouard et al. 2010. PubMed ID: 20308328). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40502/). An alternate nucleotide substitution resulting in the same missense variant (c.228G>C (p.Glu76Asp)) has been reported as pathogenic (ClinVar ID: 40503). Alternate amino acid substitutions affecting this amino acid (p.Glu76Gln, p.Glu76Ala, p.Glu76Gly, p.Glu76Val) have been interpreted as pathogenic in ClinVar (ClinVar IDs: 181496, 13339, 13338, 13337). 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 31, 2018

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;D
Eigen	Benign	-0.014
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.1	L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	D;D;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.022	D;D;.;.
Sift4G	Benign	0.13	T;T;.;T
Polyphen		0.38	B;P;.;.
Vest4		0.91
MutPred		0.89		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.99
MPC		1.7
ClinPred		0.96	D
GERP RS		1.9
Varity_R		0.89
gMVP		0.72

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: rs397507514; hg19: chr12-112888212;