rs397507540

Positions:

• chr12-112489048-C-A
• chr12-112489048-C-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1472C>A​(p.Pro491His) 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 Likely 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. P491A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 23 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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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 chr12-112489048-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 12-112489048-C-A is Pathogenic according to our data. Variant chr12-112489048-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1472C>A	p.Pro491His	missense_variant	13/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1484C>A	p.Pro495His	missense_variant	13/16
PTPN11	NM_001374625.1	c.1469C>A	p.Pro490His	missense_variant	13/16
PTPN11	XM_011538613.3	c.1481C>A	p.Pro494His	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1472C>A	p.Pro491His	missense_variant	13/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17020470, 24803665, 17546245, 30417923, 31560489) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 04, 2017	- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2015

proposed classification - variant undergoing re-assessment, contact laboratory -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Strabismus;C0349588:Short stature;C0424503:Abnormal facial shape Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Sep 02, 2021

The c.1472C>A;p.(Pro491His) variant has been published as a pathogenic variant in association with Noonan syndrome (PMID: 17546245, 21590266, 17020470; GeneOne, DASA) - PS4; ClinVar contains an entry for this variant (Variation ID: 40551); This variant is not present in population databases (rs397507540 - gnomAD no frequency; ABraOM no frequency - abraom.ib.usp.br) - PM2; Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PMID: 29493581) - PP2; In silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; Pathogenic missense variants in this residue (PMID: 20186801, 18470943, 23624134). In summary, the currently available evidence indicates that the variant is pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2018

The p.P491H pathogenic mutation (also known as c.1472C>A), located in coding exon 13 of the PTPN11 gene, results from a C to A substitution at nucleotide position 1472. The proline at codon 491 is replaced by histidine, an amino acid with similar properties. This mutation was first described in an individual meeting clinical diagnostic criteria for Noonan syndrome (Bertola DR et al. Genet. Test., 2006;10:186-91). In addition, three disease-causing mutations: p.P491L, p.P491S, and p.P491T, have been described in the same codon (Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Pierpont EI et al. Genes Brain Behav., 2009 Apr;8:275-82; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 18470943, 20186801, 22781091, 23624134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 40551). This missense change has been observed in individuals with Noonan syndrome (PMID: 17020470, 17546245, 21590266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 491 of the PTPN11 protein (p.Pro491His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.78
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.6	N;.;.
REVEL	Pathogenic	0.76
Sift	Benign	0.057	T;.;.
Sift4G	Benign	0.53	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.86
MutPred		0.89		Gain of MoRF binding (P = 0.098);.;.;
MVP		0.96
MPC		2.1
ClinPred		0.94	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.94

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: rs397507540; hg19: chr12-112926852;