12-112472961-G-T

Variant names:

• chr12-112472961-G-T
• rs397516809
• NM_002834.5:c.774G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_002834.5(PTPN11):​c.774G>T​(p.Glu258Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E258K) 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:3
• Conservation: PhyloP100: 1.59
• Publications: 7 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 15 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr12-112472959-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 982429.
• 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.
• PP5: Variant 12-112472961-G-T is Pathogenic according to our data. Variant chr12-112472961-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44613.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.774G>T	p.Glu258Asp	missense_variant	Exon 7 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.774G>T	p.Glu258Asp	missense_variant	Exon 7 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.774G>T	p.Glu258Asp	missense_variant	Exon 7 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Oct 19, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.774G>T; p.Glu258Asp variant (rs397516809) has been described in at least one individual affected with Noonan syndrome (Jongmans 2011). It is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 44613) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 258 is moderately conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, the crystal structure demonstrates that Glu258 is important in stabilizing an inhibitory interaction of two protein domains (Hof 1998), and several nearby variants have been described in individuals affected with Noonan syndrome (Binder 2005, Musante 2003, Pannone 2017). Based on available information, this variant is considered pathogenic. REFERENCES Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. Musante L et al. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet. 2003 Feb;11(2):201-6. Pannone L et al. Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome. Hum Mutat. 2017 Apr;38(4):451-459.

not provided Pathogenic:1

Oct 15, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 21407260, 29493581, 11992261, 16053901, 9491886, 38572385)

Noonan syndrome Pathogenic:1

Feb 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu258Asp variant in PTPN11 has been reported in 3 Dutch individuals with Noonan syndrome (Jongmans 2011) and identified by our laboratory in 1 Ashkenazi Jewish adult with a clinical diagnosis of Noonan syndrome (LMM, unpublished data ). It was absent from large population studies. Computational prediction tools a nd conservation analysis suggest that this variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, although additional studies are required to fully establish its clinical sig nificance, the p.Glu369Asp variant is likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.29
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		1.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	D;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.17	T;T;.
Sift4G	Benign	0.16	T;T;T
Vest4		0.90
ClinPred		0.84	D
GERP RS		-0.48
Varity_R		0.87
gMVP		0.46
Mutation Taster		=5/95	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: rs397516809; hg19: chr12-112910765; COSMIC: COSV105261512; COSMIC: COSV105261512;