12-112489081-C-T

Position:

• chr12-112489081-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1505C>T​(p.Ser502Leu) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S502A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) 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 chr12-112489080-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ: 3.1293 (greater than the threshold 3.09). Trascript score misZ: 4.9438 (greater than threshold 3.09). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. GenCC has associacion of the gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 12-112489081-C-T is Pathogenic according to our data. Variant chr12-112489081-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489081-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1505C>T	p.Ser502Leu	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1517C>T	p.Ser506Leu	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1502C>T	p.Ser501Leu	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1514C>T	p.Ser505Leu	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1505C>T	p.Ser502Leu	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1517C>T	p.Ser506Leu	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.518C>T	p.Ser173Leu	missense_variant	5/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	Not observed 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 often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 28628100, 28084675, 24030381, 18948947, 17910045, 15385933, 28183348, 26918529, 18470943, 17020470, 16358218, 19020799, 24803665, 28991257, 30050098, 30287924, 29907801, 32164556, 31115076, 33318624, 29493581, 32368696) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PTPN11: PS2:Very Strong, PM2, PM5, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Noonan syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PS2+PP2+PP3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0251 - This variant is heterozygous. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Both the p.(Ser502Ala) and the p.(Ser502Thr) have been previously reported in patients with Noonan syndrome (ClinVar, PMID: 18470943, PMID: 11992261). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Noonan syndrome (ClinVar, PMID: 18470943, PMID: 11992261, PMID: 28084675 and PMID: 32164556). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong	Jul 22, 2021	This variant c.1505C>T(p.S502L) has been reported in multiple unrelated pateints with Noonan spectrum disorders [PMID: 22465605, 17020470, 32164556, 26918529, 28991257, 24803665, 29907801, 15385933, 30287924] and was reported to be de novo in at least one case (PS2). Missense variants in the same residue and nearby residues have been reported in multiple individuals with Noonan spectrum disorders (PMID: 16358218, 26242988, 23832011) (PM1). This variant is currently absent in the gnomAD database (PM2). Computational evidence support a deleterious effect on the gene product (PP3). This variant has been classified as pathogenic by multiple labs in ClinVar [Variation ID: 40557] (PP5). This variant is interpreted as pathogenic according to ACMG/AMP guidelines. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser502 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12325025, 15928039, 18470943, 23832011, 26242988, 27521173). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40557). This missense change has been observed in individuals with Noonan syndrome or LEOPARD syndrome (PMID: 17020470, 19020799). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 502 of the PTPN11 protein (p.Ser502Leu). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2021	Variant summary: PTPN11 c.1505C>T (p.Ser502Leu) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, there are several variants associated with disease at the same codon or surrounding codons (e.g., S502A, S502T, R501K, and G503A), suggesting the region is important for protein function. Serine at position 502 interacts with Glutamate at position 76 in the SH2 domain, leading to autoinhibition of PTPN11, and mutational hotspot variants at Serine 502 or Glutamate 76 were shown to activate PTPN11 (example, Chan_2007, PMID 17053061). The variant was absent in 252092 control chromosomes. c.1505C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (example, Tartaglia_2006, Bertola_2006, Ezquieta_2012, Strullu_2014, Ko_2008, O'Halloran_2017). At-least one report of a reportedly de-novo occurrence was ascertained in the context of this evaluation (Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 15, 2013

The Ser502Leu variant has been reported in the literature in two individuals wit h clinical features of Noonan syndrome and/or LEOPARD syndrome (Tartaglia 2006, Ko 2008). Our laboratory has identified this variant in one proband where parent al testing was performed and showed the variant occurred de novo (LMM unpublishe d data). This variant has also been identified as a somatic variant in individua ls with hematologic malignancies including AML and ALL (Goemans 2005, Paulsson 2 007). In addition, three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Ala) have been associated with the clinical features of Noonan syndrome and have also been identified as somatic variants in individuals with h ematologic malignancies (Aoki 2008). The Ser502 residue is conserved across spec ies and computational analyses (biochemical amino acid properties, AlignGVGD, Po lyPhen2, and SIFT) suggest that the Ser502Leu variant may impact the normal func tion of the protein. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon the de novo occurrenc e combined with available published literature. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.024	D;D;T
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.86		Loss of disorder (P = 0.0054);.;.;
MVP		1.0
MPC		1.8
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		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507544; hg19: chr12-112926885; COSMIC: COSV61005111; COSMIC: COSV61005111;