12-112489093-A-C

Variant names:

• chr12-112489093-A-C
• rs397507548
• NM_002834.5:c.1517A>C

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1 PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1517A>C​(p.Gln506Pro) 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000253878: Experimental studies have shown that this missense change affects PTPN11 function (PMID:15987685, 24935154, 26742426)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 8.95
• Publications: 64 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Noonan syndrome

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

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

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124903024 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000253878: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 24935154, 26742426).; SCV001448393: Functional studies report this variant exhibits reduced catalytic activity (Yu_2014, Qiu_2014).; SCV006336785: Enzyme-catalyzed hydrolysis of p-nitrophenyl phosphate analysis in E. Coli indicated reduced catalytic speed for the mutant. A study in HEK293 cells showed that the mutant performed dephosphorylation with greater efficiency and exhibited atypical behavior in ERK pathways. Another analysis in E. Coli showed increased dephosphorylation in the mutant. Each of these three assays indicate that the variant impacts protein function (PS3_moderate; PMIDs: 24935154, 26742426).; SCV000057455: Published functional studies demonstrate p.(Q506P) affects the catalytic phosphatase domain (PTP) of the protein and interferes with its normal phosphatase activity (Qiu et al., 2014; Yu et. al, 2014);; SCV002107107: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987685; 24935154; 26742426) - PS3."; SCV002708581: Structural and functional studies indicate that this mutation results in a weakened auto-inhibited enzyme conformation leading to prolonged substrate turnover, producing a gain-of-function rasopathy phenotype through sustained activation of the RAS-ERK pathway (Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51).; SCV001984808: "In-vitro functional assessment of this alteration revealed that it affects the normal phosphatase activity of the protein." PMID:15987685, PMID:24935154, PMID:24628801; SCV004765765: Functional and structural studies found this variant inhibits catalytic activity (Keilhack et al. 2005. PubMed ID: 15987685; Qiu et al. 2014. PubMed ID: 24628801; Yu et al. 2014. PubMed ID: 24935154).; SCV005044131: Published functional studies have shown reduced catalytic phosphatase activity of protein carrying the p.(Gln506Pro) variant [PMID: 15987685, 24628801, 24935154, 26742426].; SCV005438811: Experimental studies have shown that this missense change affects PTPN11 function Noda et al., 2016.
• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• 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 LEOPARD syndrome 1, metachondromatosis, Noonan syndrome with multiple lentigines, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-112489093-A-C is Pathogenic according to our data. Variant chr12-112489093-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 40563.Status of the report is reviewed_by_expert_panel, 3 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.1517A>C	p.Gln506Pro	missense	Exon 13 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.1529A>C	p.Gln510Pro	missense	Exon 13 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.1514A>C	p.Gln505Pro	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.1517A>C	p.Gln506Pro	missense	Exon 13 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1529A>C	p.Gln510Pro	missense	Exon 13 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000635652.1	TSL:3	c.530A>C	p.Gln177Pro	missense	Exon 5 of 5	ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	RASopathy (3)
2	-	-	Noonan syndrome 1 (2)
2	-	-	PTPN11-related disorder (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Congenital long QT syndrome (1)
1	-	-	Noonan syndrome (1)
1	-	-	Noonan syndrome with multiple lentigines (1)
-	-	-	LEOPARD syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.87	P
Vest4		0.98
MutPred		0.98		Loss of MoRF binding (P = 0.057)
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=12/88	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: rs397507548; hg19: chr12-112926897; COSMIC: COSV61007665; COSMIC: COSV61007665;