rs397507511

Variant names:

• chr12-112450385-G-A
• rs397507511
• NM_002834.5:c.205G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-112450385-G-A
• chr12-112450385-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.205G>A​(p.Glu69Lys) 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. E69Q) 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:3 U: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 domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 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 chr12-112450385-G-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, 0.862
• PP5: Variant 12-112450385-G-A is Pathogenic according to our data. Variant chr12-112450385-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224414.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr12-112450385-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.205G>A	p.Glu69Lys	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.205G>A	p.Glu69Lys	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.205G>A	p.Glu69Lys	missense_variant	Exon 3 of 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:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Noonan syndrome 1 Pathogenic:1

-

Centogene AG - the Rare Disease Company

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Aug 02, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PTPN11 c.205G>A (p.Glu69Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant, to our knowledge, has not been reported in the medical literature in individuals with Noonan syndrome. This variant has been reported in the ClinVar database as a likely pathogenic variant by two submitters and a germline variant of uncertain significance by one submitter (ClinVar Variation ID: 224414). The PTPN11 c.205G>A (p.Glu69Lys) variant has been reported in numerous types of cancers in the cancer database COSMIC (Genomic Mutation ID: COSV61004768). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. Other variants in the same codon (c.205G>C (p.Glu69Gln), c.206A>T (p.Glu69Val), c.206A>C (p.Glu69Ala) have been reported in individuals affected with Noonan syndrome (Musante L et al., PMID:12634870; Atik Tet al., PMID: 26817465; Pierpont E et al., PMID: 20186801; ClinVar ID: 1997356). This variant resides within a region, the N-SH2 domain, amino acids 1-104, of PTPN11 that is defined as a critical functional domain (Musante L et al., PMID:12634870; Gelb BD et al., PMID: 29493581; Tartaglia M et al., PMID: 11992261; Hof P et al., PMID: 9491886; Zenker M al., PMID: 15001945). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PTPN11 function. In support of this prediction, functional studies show that this variant promotes interactions between the N-SH2 domain and upstream signaling molecules by inducing a conformational change to an open state, allowing substrate entry into the catalytic site and thereby enhancing ERK signaling (Eminaga S et al., PMID: 18378677; Liu X et al., PMID: 21799948; Bocchinfuso G et al., PMID: 17177198; Fragale A et al., PMID: 14974085). The PTPN11 gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PTPN11 c.205G>A (p.Glu69Lys) variant is classified as likely pathogenic. -

not provided Pathogenic:1

Sep 22, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Mar 10, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E69K variant (also known as c.205G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 205. The glutamic acid at codon 69 is replaced by lysine, an amino acid with similar properties. This alteration has been described as an acquired somatic change in multiple cancer types, including: juvenile myelomonocytic leukemia (JMML), acute lymphoblastic leukemia (ALL), neuroblastoma, and astrocytoma (Loh ML et al. Blood, 2004 Mar;103:2325-31; Tartaglia M et al. Blood, 2004 Jul;104:307-13; Bentires-Alj M et al. Cancer Res., 2004 Dec;64:8816-20; Jones DT et al. Nat. Genet., 2013 Aug;45:927-32). In vivo functional studies have shown that this alteration results in increased and phosphatase activity compared to wild-type (Bentires-Alj M et al. Cancer Res., 2004 Dec;64:8816-20; Eminaga S et al. J. Biol. Chem., 2008 May;283:15328-38). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. There have been no reports of individuals clinically affected with Noonan syndrome or related disorders; since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.73
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;.;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.5	L;L;.;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D;D;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.021	D;D;.;D
Polyphen		0.99	D;D;.;.
Vest4		0.89
MutPred		0.69		Gain of ubiquitination at E69 (P = 0.0185);Gain of ubiquitination at E69 (P = 0.0185);Gain of ubiquitination at E69 (P = 0.0185);Gain of ubiquitination at E69 (P = 0.0185);
MVP		0.86
MPC		1.1
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.81

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: rs397507511; hg19: chr12-112888189; COSMIC: COSV61004768; COSMIC: COSV61004768;