chr12-112473033-C-G

Position:

• chr12-112473033-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.846C>G​(p.Ile282Met) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I282V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: -0.00200

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 17 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) 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 chr12-112473031-A-G is described in Lovd as [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, 0.923
• PP5: Variant 12-112473033-C-G is Pathogenic according to our data. Variant chr12-112473033-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112473033-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.846C>G	p.Ile282Met	missense_variant	7/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.846C>G	p.Ile282Met	missense_variant	7/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.846C>G	p.Ile282Met	missense_variant	7/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447352 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.846C>G;p.(Ile282Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40526; PMID: 26817465; 23917401) - PS4.This variant is not present in population databases (rs397507530, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 40525) - PM5. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 18, 2019	ACMG codes: PS4M, PM2, PP3, PP5 -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2022	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; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21934682, 23917401, 25742478, 26817465, 31560489, 34006472) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PTPN11: PM1, PM2, PS2:Moderate, PS4:Moderate, PP2, PP3 -

Noonan syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2018	The p.Ile282Met variant in PTPN11 has been reported in 3 individuals with clinic al features of Noonan syndrome and was inherited from an affected parent in one of these cases (Atik 2016, Klapecki 2005, LMM unpublished data). This variant wa s absent from large population studies. It has been reported in ClinVar (Variat ion ID 40526) and has been reported as a somatic variant in a glioblastoma (Frat tini 2013). Computational prediction tools and conservation analysis suggest th at this variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. Furthermore, another variant at this positi on (p.Ile282Val) has been reported in multiple individuals with clinical feature s of Noonan syndrome and is classified as pathogenic by our laboratory and in Cl inVar (Variation ID 40525). In summary, although additional studies are required to fully establish its clinical significance, the p.Ile282Met variant is likely pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: P M2, PM5, PP3, PS4_Supporting. -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

The PTPN11 c.846C>G variant is predicted to result in the amino acid substitution p.Ile282Met. This variant has been reported as both de novo and inherited in individuals with Noonan syndrome (Atik et al. 2016. PubMed ID: 26817465; Chinton et al. 2019. PubMed ID: 31560489; reported as de novo in Table S3, Fan et al. 2021. PubMed ID: 34006472; Table S2, Bowling et al. 2021. PubMed ID: 34930662). Alternate substitutions of this amino acid (p.Ile282Val and p.Ile282Thr) have also been reported in individuals with Noonan syndrome (Tartaglia et al. 2001. PubMed ID: 11704759; Table S1, Ziats et al. 2020. PubMed ID: 31618753). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been listed as pathogenic or likely pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40526/). Given the evidence, we interpret this variant as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2020

The p.I282M variant (also known as c.846C>G), located in coding exon 7 of the PTPN11 gene, results from a C to G substitution at nucleotide position 846. The isoleucine at codon 282 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in subjects who have a phenotype consistent with Noonan syndrome (Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Kruszka P et al. Am. J. Med. Genet. A, 2017 Sep;173:2323-2334; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337; Castellanos E et al. Clin. Genet., 2020 02;97:264-275; Ambry internal data). A different amino acid substitution at the same position, p.I282V, has been documented in two unrelated individuals with Noonan syndrome (Tartaglia M, et al. Nat. Genet. 2001;29(4):465-8. Jongmans MC, et al. Eur. J. Hum. Genet. 2011;19(8):870-4). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile282 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 15834506, 19077116, 21407260). 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) 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. ClinVar contains an entry for this variant (Variation ID: 40526). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26817465, 31560489, 34006472). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 282 of the PTPN11 protein (p.Ile282Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.79
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	.;.;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	4.0	H;H;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.77		Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		1.3
Varity_R		0.88
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397507530; hg19: chr12-112910837; COSMIC: COSV61005312; COSMIC: COSV61005312;