12-112473023-A-G

Variant names:

• chr12-112473023-A-G
• rs121918456
• NM_002834.5:c.836A>G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.836A>G​(p.Tyr279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 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: "SCV000053298: Multiple functional studies have indicated the variant abolishes enzymatic activity of PTPN11 and increases AKT, the variant's mechanism causes a gain of function (Yu_2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y279S) has been classified as Likely pathogenic. The gene PTPN11 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:34 O:1
• Conservation: PhyloP100: 8.95
• Publications: 146 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

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: SCV000053298: Multiple functional studies have indicated the variant abolishes enzymatic activity of PTPN11 and increases AKT, the variant's mechanism causes a gain of function (Yu_2014).; SCV000287695: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 16638574, 18372317, 21339643, 23673659).; SCV005438754: Published functional studies demonstrate weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation Yu et al., 2014; Kontaridis et al., 2006.; SCV000057409: Published functional studies demonstrate weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation (Yu et al., 2014; Kontaridis et al., 2006); SCV002817210: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16358218, 16638574, 16377799, 18372317); SCV000739978: "In addition, a functional study of fibroblasts from individuals heterozygotes for this mutation, and HEK293 cells transfected with this mutation, showed significantly stronger EGF-induced phosphorylation of downstream targets when compared to normal controls (Edouard T, Mol. Cell. Biol. 2010 May; 30(10):2498-507)."; SCV000898916: "In addition, functional studies (including a drosophila model) have shown a deleterious effect of this variant (Kontaridis 2006 PMID: 16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586)."; SCV001157828: biochemical analyses demonstrate strongly reduced phosphatase activity of the p.Tyr279Cys variant (Hanna 2006, Qiu 2014).; SCV004110551: Functional studies demonstrate increased p-MEK/ERK levels, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Kontaridis et al. 2006. PubMed ID: 16377799; Hanna et al. 2006. PubMed ID: 16638574; Martinelli et al. 2008. PubMed ID: 18372317; Schramm et al. 2013. PubMed ID: 23673659; Yu et al. 2014. PubMed ID: 24935154).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 chr12-112473023-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.993
• PP5: Variant 12-112473023-A-G is Pathogenic according to our data. Variant chr12-112473023-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13328.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.836A>G	p.Tyr279Cys	missense	Exon 7 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.836A>G	p.Tyr279Cys	missense	Exon 7 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.833A>G	p.Tyr278Cys	missense	Exon 7 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.836A>G	p.Tyr279Cys	missense	Exon 7 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.836A>G	p.Tyr279Cys	missense	Exon 7 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.836A>G	p.Tyr279Cys	missense	Exon 7 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454492 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723992

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105576

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000107 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	LEOPARD syndrome 1 (10)
8	-	-	not provided (8)
4	-	-	Noonan syndrome 1 (4)
4	-	-	RASopathy (4)
2	-	-	PTPN11-related disorder (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	CBL-related disorder (1)
1	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome with multiple lentigines (1)
1	-	-	Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.085	T
Polyphen		0.85	P
Vest4		0.98
MutPred		0.94		Loss of phosphorylation at Y279 (P = 0.0853)
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.83
Mutation Taster		=0/100	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: rs121918456; hg19: chr12-112910827; COSMIC: COSV61009292; COSMIC: COSV61009292;