rs121918464

Variant names:

• chr12-112450406-G-A
• rs121918464
• NM_002834.5:c.226G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-112450406-G-A
• chr12-112450406-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_002834.5(PTPN11):​c.226G>A​(p.Glu76Lys) 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 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:9 U:2 O:1
• Conservation: PhyloP100: 9.99

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 10 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 the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.921
• PP5: Variant 12-112450406-G-A is Pathogenic according to our data. Variant chr12-112450406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13336.We mark this variant Likely_pathogenic, oryginal submissions are: {other=1, Uncertain_significance=1, Pathogenic=6}. Variant chr12-112450406-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.226G>A	p.Glu76Lys	missense_variant	Exon 3 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.226G>A	p.Glu76Lys	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.226G>A	p.Glu76Lys	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Jun 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in published literature in patients with juvenile myelomonocytic leukemia (Kratz et al., 2005); Reported in published literature in association with somatic hematologic malignancies (Tartaglia et al., 2006); Published functional studies demonstrate a damaging effect on protein function and structure (Tartaglia et al., 2006; Gagne-Sansfaon et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22391158, 17177198, 29206716, 27582544, 15928039, 16358218, 9491886, 16053901, 11992261, 29493581, 27535533, 27783593, 23825065, 31222725, 15842656, 15385933, 14982869, 32697817, 12717436, 21930766, 19047918, 18470943, 14644997) -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11: PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting -

Apr 09, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Pathogenic:2

Jun 21, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu76Lys variant in PTPN11 is an established pathogenic variant that has been identified as a somatic change in >40 individuals with JMML (Tartaglia 2003, Loh 2004, Kratz 2005, Tartaglia 2005, Aoki 2008, Yoshida 2009) and is absent from large population studies. In vitro and in vivo functional studies show that this variant has a strong gain of function impact (Tartaglia 2003, Loh 2004, Xu 2011, Yu 2013, Chang 2016, Dong 2016). Several other variants involving this codon have been identified in individuals with Noonan syndrome and/or hematological malignancies. In summary, this variant meets criteria to be classified as pathogenic for JMML. -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

RASopathy Pathogenic:1 Uncertain:1

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 76 of the PTPN11 protein (p.Glu76Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (JMML) (PMID: 12717436, 14644997, 14982869). ClinVar contains an entry for this variant (Variation ID: 13336). 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: 14974085, 19509418). 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). 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. -

-

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Noonan syndrome 1 Pathogenic:1

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTPN11-related disorder Pathogenic:1

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been previously reported as a germline variant to our knowledge; however, it has been observed as a somatic variant in individuals with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (PMID:14644997, 14982869, 12717436). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with PTPN11 - related disorders. Different amino acid changes at the same residue (p.Glu76Asp, p.Glu76Gln, p.Glu76Gly, p.Glu76Val) have been previously reported in individuals with Noonan syndrome and/or hematological malignancies (PMID: 16830086, 11704759, 18678287, 12634870). Functional studies showed that the c.226G>A (p.Glu76Lys) variant has a gain-of-function effect on the PTPN11 protein (PMID: 14974085, 19509418, 27783593). It is absent from the gnomAD population database and thus is presumed to be rare. The c.226G>A (p.Glu76Lys) variant 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.226G>A (p.Glu76Lys) variant is classified as Pathogenic. -

Noonan syndrome Pathogenic:1

May 10, 2013

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant neoplastic disease Uncertain:1

-

Investigational Cancer Therapeutics, MD Anderson Cancer Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D;D;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D;D;.;.
Sift4G	Uncertain	0.012	D;D;.;D
Polyphen		0.99	D;D;.;.
Vest4		0.94
MutPred		0.76		Gain of methylation at E76 (P = 0.0223);Gain of methylation at E76 (P = 0.0223);Gain of methylation at E76 (P = 0.0223);Gain of methylation at E76 (P = 0.0223);
MVP		0.99
MPC		2.0
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.88

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: rs121918464; hg19: chr12-112888210; COSMIC: COSV61004889; COSMIC: COSV61004889;