rs397507518

Variant names:

• chr12-112450508-G-A
• rs397507518
• NM_002834.5:c.328G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_002834.5(PTPN11):​c.328G>A​(p.Glu110Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E110G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 9.59
• Publications: 10 publications found

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]

PTPN11 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr12-112450509-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1339747.
• 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 Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 12-112450508-G-A is Pathogenic according to our data. Variant chr12-112450508-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.328G>A	p.Glu110Lys	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.328G>A	p.Glu110Lys	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.328G>A	p.Glu110Lys	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome Pathogenic:1 Uncertain:1

Nov 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu110Lys variant in PTPN11 has been previously identified in three indivi duals with clinical features of Noonan syndrome (Ezquieta 2012, Rodriguez 2014, LMM unpublished data) and was reported to have occurred de novo in two of these individuals (Ezquieta 2012, LMM unpublished data). It was absent from large popu lation studies (http://evs.gs.washington.edu/EVS/; dbSNP rs397507518). In summar y, the p.Glu110Lys variant in PTPN11 meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/). -

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome 1 Pathogenic:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.328G>A (p.Glu110Lys) variant in the PTPN11 gene which is located in a mutational hot spot has been reported previously in a heterozygous state in individuals affected with Noonan syndrome (Lepri et al., 2014; Rodríguez et al., 2014). Different amino acid change affecting codon 110 (p.Glu110Ala) is reported as a known pathogenic variant. The glutamic acid 110 localizes at the linker stretch, which connects the N-SH2 and C-SH2 domains of SHP-2. Mutations affecting this linker are predicted to alter the relative orientation or mobility of N-SH2, which may abrogate its autoinhibitory function (Tartaglia et al., 2006; Rodríguez et al., 2014). The amino acid Glutamic Acid at position 110 is changed to a Lysine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Glu110Lys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Aug 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 22465605, 29907801, 24451042, 30050098, 35769956, 24150203, 29493581, 35979676) -

Noonan syndrome 3 Pathogenic:1

Mar 14, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Nov 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E110K variant (also known as c.328G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 328. The glutamic acid at codon 110 is replaced by lysine, an amino acid with similar properties. This variant was detected in multiple individuals with features consistent with PTPN11-related RASopathy; in at least individual, it was reported to have occurred de novo (Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Lepri FR et al. BMC Med Genet, 2014 Jan;15:14; Rodríguez FA et al. J. Pediatr. Endocrinol. Metab., 2014 Mar;27:305-9; Elmas M et al. J Pediatr Genet, 2022 Jun;11:110-116; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Gain-of-function variants in PTPN11 are known to cause RASopathy; however, such associations with metachondromatosis have not been observed (Bowen ME et al. PLoS Genet, 2011 Apr;7:e1002050). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation for PTPN11-related RASopathy; however, it is unlikely to be causative of metachondromatosis. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Aug 07, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Aug 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in individuals affected with Noonan syndrome in the literature, including at least one individual where the variant was reported de novo (PMID: 22465605, 24150203, 24451042). ClinVar contains an entry for this variant (Variation ID: 40507). This sequence change replaces glutamic acid with lysine at codon 110 of the PTPN11 protein (p.Glu110Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	.;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.2	M;M;.;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.6	D;D;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Uncertain	0.014	D;D;.;D
Polyphen		0.90	P;D;.;.
Vest4		0.95
MutPred		0.67		Gain of methylation at E110 (P = 0.01);Gain of methylation at E110 (P = 0.01);Gain of methylation at E110 (P = 0.01);Gain of methylation at E110 (P = 0.01);
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.96
gMVP		0.87
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397507518; hg19: chr12-112888312;