chr12-112450416-A-G

Variant names:

• chr12-112450416-A-G
• rs121918466
• NM_002834.5:c.236A>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.236A>G​(p.Gln79Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,582 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001451638: Functional studies in HEK293 cells, rat cardiomyocytes and chick valve explants found that the p.Gln79Arg is a gain-of-function variant resulting in increased MAPK 1/2 signaling and thereby increased growth, which can be reversed by use of MAPK 1/2 inhibitors (Niihori et al. 2005; Krenz et al. 2005).; SCV005044112: Functional studies suggest that the p.Gln79Arg variant increases ERK1/2 signaling [PMID:16166557].; SCV000253880: Experimental studies have shown that this missense change affects PTPN11 function (PMID:16166557, 17641779, 19017799).; SCV000061303: "In-vivo animal models and in-vitro studies provide evidence that the p.Gln79Arg variant impacts protein function (Krenz 2005, Nakamura 2007)."; SCV000057385: In vitro expression of PTPN11-Q79R in cardiac cell cushions from chick embryos resulted in increased phosphatase activity and significantly increased outgrowth of cushion cells compared to wild-type protein expression (Krenz et al., 2005).; SCV005417156: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000698073: In vitro studies show that this mutant results in significantly elevated phosphatase activity and endocardial cushion growth (Krenz_2005). Furthermore, in vivo mice expression model showed that this mutant leads to embryonic lethality and the embryonic hearts showed altered cardiomyocyte cell cycling ventricular noncompaction, and ventricular septal defects. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2 (Nakamura_2007).; SCV002735849: Activity studies in rat neonatal cardiomyocytes showed this alteration results in a gain-of-function of the protein, with a 4.5 times higher activity compared to wild type (Krenz, 2005).; SCV004046235: Functional studies showed that the c.236A>G (p.Gln79Arg) variant is a gain-of-function variant that induces an increase of phosphatase activity and endocardial cushion growth (PMID:16166557, 15834506).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q79K) 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 criteria provided, multiple submitters, no conflicts P:32
• Conservation: PhyloP100: 9.31
• 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

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001451638: Functional studies in HEK293 cells, rat cardiomyocytes and chick valve explants found that the p.Gln79Arg is a gain-of-function variant resulting in increased MAPK 1/2 signaling and thereby increased growth, which can be reversed by use of MAPK 1/2 inhibitors (Niihori et al. 2005; Krenz et al. 2005).; SCV005044112: Functional studies suggest that the p.Gln79Arg variant increases ERK1/2 signaling [PMID:16166557].; SCV000253880: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16166557, 17641779, 19017799).; SCV000061303: "In-vivo animal models and in-vitro studies provide evidence that the p.Gln79Arg variant impacts protein function (Krenz 2005, Nakamura 2007)."; SCV000057385: In vitro expression of PTPN11-Q79R in cardiac cell cushions from chick embryos resulted in increased phosphatase activity and significantly increased outgrowth of cushion cells compared to wild-type protein expression (Krenz et al., 2005).; SCV005417156: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000698073: In vitro studies show that this mutant results in significantly elevated phosphatase activity and endocardial cushion growth (Krenz_2005). Furthermore, in vivo mice expression model showed that this mutant leads to embryonic lethality and the embryonic hearts showed altered cardiomyocyte cell cycling ventricular noncompaction, and ventricular septal defects. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2 (Nakamura_2007).; SCV002735849: Activity studies in rat neonatal cardiomyocytes showed this alteration results in a gain-of-function of the protein, with a 4.5 times higher activity compared to wild type (Krenz, 2005).; SCV004046235: Functional studies showed that the c.236A>G (p.Gln79Arg) variant is a gain-of-function variant that induces an increase of phosphatase activity and endocardial cushion growth (PMID: 16166557, 15834506).
• PM1: In a hotspot region, there are 20 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 chr12-112450415-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 44605.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, 0.964
• PP5: Variant 12-112450416-A-G is Pathogenic according to our data. Variant chr12-112450416-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13340.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.236A>G	p.Gln79Arg	missense	Exon 3 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.236A>G	p.Gln79Arg	missense	Exon 3 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.233A>G	p.Gln78Arg	missense	Exon 3 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.236A>G	p.Gln79Arg	missense	Exon 3 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.236A>G	p.Gln79Arg	missense	Exon 3 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.236A>G	p.Gln79Arg	missense	Exon 3 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461582 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

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

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111764

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000496 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Noonan syndrome 1 (13)
7	-	-	not provided (7)
3	-	-	Noonan syndrome (3)
2	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (2)
2	-	-	PTPN11-related disorder (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Monogenic short statue (1)
1	-	-	Noonan syndrome 3 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.11	T
Polyphen		0.85	P
Vest4		0.93
MutPred		0.90		Loss of helix (P = 0.1299)
MVP		1.0
MPC		1.9
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.72
Mutation Taster		=6/94	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: rs121918466; hg19: chr12-112888220; COSMIC: COSV61005872; COSMIC: COSV61005872;