12-112450407-A-G

Position:

• chr12-112450407-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_002834.5(PTPN11):​c.227A>G​(p.Glu76Gly) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.31

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 12 ACMG points.

• 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, 0.947
• PP5: Variant 12-112450407-A-G is Pathogenic according to our data. Variant chr12-112450407-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13338.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr12-112450407-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.227A>G	p.Glu76Gly	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.227A>G	p.Glu76Gly	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.227A>G	p.Glu76Gly	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Juvenile myelomonocytic leukemia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2015	The p.Glu76Gly variant in PTPN11 has been reported as a somatic change in >10 in dividuals with juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia ( AML), or childhood acute lymphoblastic leukemia (ALL; Tartaglia 2003, Tartaglia 2004, Loh 2004, Kratz 2005). In addition, many other variants at this position h ave been frequently identified as a somatic change in individuals with JMML, AML , and ALL, and codon 76 in PTPN11 has been described as the mutational hot-spot for JMML (Tartaglia 2003). It was absent from large population studies. In summa ry, this variant meets our criteria to be classified as pathogenic for JMML. -

RASopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2023	Variant summary: PTPN11 c.227A>G (p.Glu76Gly) results in a non-conservative amino acid change located in the SH2 domain 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 251068 control chromosomes. c.227A>G has been reported in the literature in individuals affected with Noonan Syndrome or Juvenile myelomonocytic leukemia (examples: Unal_2010, Timeus_2013, Mason-Suares_2017). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Ren_2007, Niihori_2005, Lee_2008, Tien_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23756559, 19798502, 36349709, 28098151, 17942397, 15834506, 18559669, 26783207, 19179468). Two ClinVar submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 76 of the PTPN11 protein (p.Glu76Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with somatic juvenile myelomonocytic leukemia and a fetus with a heart defect, hydrops, and persistent cystic hygroma (PMID: 12717436, 14644997, 21901340, 23756559, 23832011, 28098151). ClinVar contains an entry for this variant (Variation ID: 13338). 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) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Glu76 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2018

The E76G pathogenic variant in the PTPN11 gene lies within the region coding for the N-SH2 domain, which is a hot spot for mutations in Noonan syndrome (Tartaglia et al., 2001 and Tartaglia et al., 2006). The E76G is not observed in large population cohorts (Lek et al., 2016). It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Another amino acid substitution at codon 76, E76D, has been reported as germline pathogenic variant in approximately 3% of individuals with Noonan syndrome (Kratz et al., 2005). Other missense variants at the same codon have also been reported as somatic variants in association with juvenile myelomonocytic leukemia (JMML) and other hematologic malignancies (Shimada et al., 2004 and Tartaglia et al., 2006). It has been hypothesized that residues with strong associations to isolated JMML, like this variant, often result in embryonic lethal or severe clinical presentations if inherited as a germline variant (Mason-Suares et al., 2017, Tartaglia et al., 2006; Lee KA et al., 2009, Chan RJ, et al., 2007 Tartaglia M, et al., 2003). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.0	D;D;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.030	D;D;.;D
Polyphen		0.94	P;D;.;.
Vest4		0.95
MutPred		0.81		Gain of catalytic residue at A75 (P = 0.0151);Gain of catalytic residue at A75 (P = 0.0151);Gain of catalytic residue at A75 (P = 0.0151);Gain of catalytic residue at A75 (P = 0.0151);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.84

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: rs121918465; hg19: chr12-112888211; COSMIC: COSV61005372; COSMIC: COSV61005372;