12-112489104-C-G

Variant names:

• chr12-112489104-C-G
• rs397507549
• NM_002834.5:c.1528C>G
• PTPN11 p.Gln510Glu

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 23 ACMG points: 23P and 0B. PS3PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):​c.1528C>G​(p.Gln510Glu) 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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000776867: Experimental studies have shown that this missense change affects PTPN11 function (PMID:21803945, 22058153, 23673659, 24935154, 25708222, 26742426)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q510L) has been classified as Likely pathogenic. The gene PTPN11 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.57
• Publications: 77 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), PanelApp Australia, G2P, Genomics England PanelApp
• Noonan syndrome

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

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

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124903024 (HGNC:):

ACMG classification

Specifications for PTPN11 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000776867: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 21803945, 22058153, 23673659, 24935154, 25708222, 26742426).; SCV000057458: Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012);; SCV000698058: Animal model studies concluded that cardiomyocyte-specific expression of Q510E-Shp2 was sufficient to induce the HCM phenotype.; SCV000739999: assays in both in vitro and in vivo models have demonstrated disrupted PTPN11 protein function for p.Q510E, and resultant hypertrophic cardiomyopathy (Ishida H et al. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1531-9; Schramm C et al. Am. J. Physiol. Heart Circ. Physiol. 2012;302:H231-43; Yu ZH et al. Biochemistry. 2014;53:4136-51; Noda S et al. Biochem. Biophys. Res. Commun. 2016;469:1133-9).; SCV001244986: Functional analysis of cardiomyocyte cell lines demonstrated significant attenuation of myofibrillogenesis and increased proliferation, whilst mice overexpressing this variant showed increased cardiomyocyte size, heart-to-body weight ratios, interventricular septum thickness, cardiomyocyte disarray, thickened ventricular walls and depressed contractile function (Ishida, H., et al. (2011), Schramm, C., et al. (2012)).; SCV000203937: animal models in mice have shown that this variant causes hypertrophic cardiomyopathy (Schramm 2012).; SCV004046160: "In-vitro studies have shown that this missense change abolishes PTPN11 phosphatase activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222), and mouse models have demonstrated altered cardiac function (PMID: 22058153)."
• PM1: In a hotspot region, there are 14 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 chr12-112489105-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 981537.
• 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, LEOPARD syndrome 1, metachondromatosis, Noonan syndrome 1, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, Costello syndrome.
• PP3: REVEL computational evidence supports a deleterious effect, 0.958
• PP5: Variant 12-112489104-C-G is Pathogenic according to our data. Variant chr12-112489104-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.1528C>G	p.Gln510Glu	missense	Exon 13 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.1540C>G	p.Gln514Glu	missense	Exon 13 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.1525C>G	p.Gln509Glu	missense	Exon 13 of 16	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.1528C>G	p.Gln510Glu	missense	Exon 13 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1540C>G	p.Gln514Glu	missense	Exon 13 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000635652.1	TSL:3	c.541C>G	p.Gln181Glu	missense	Exon 5 of 5	ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Noonan syndrome 1 (5)
3	-	-	RASopathy (3)
2	-	-	PTPN11-related disorder (2)
1	-	-	Autosomal dominant PTPN11-related disorders (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome 3 (1)
1	-	-	Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines (1)
1	-	-	See cases (1)
-	-	-	LEOPARD syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=9/91	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397507549;

hg19: chr12-112926908;

COSMIC: COSV61007076;

COSMIC: COSV61007076;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline