rs397507543

Positions:

• chr12-112489078-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1502G>A​(p.Arg501Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.60

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 17 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
• 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, 0.989
• PP5: Variant 12-112489078-G-A is Pathogenic according to our data. Variant chr12-112489078-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1502G>A	p.Arg501Lys	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1514G>A	p.Arg505Lys	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1499G>A	p.Arg500Lys	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1511G>A	p.Arg504Lys	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1502G>A	p.Arg501Lys	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1514G>A	p.Arg505Lys	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.515G>A	p.Arg172Lys	missense_variant	5/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2022	Identified in several unrelated patients with Noonan syndrome in published literature (Tartaglia et al., 2002; Limal et al., 2006; Noordam et al., 2008; Jefferies et al., 2010); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19795160, 24803665, 18562489, 11992261, 16263833, 18470943, 31134136, 33726816, 35325944) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2022	PP2, PP3, PM2_supporting, PS4 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Noonan syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jun 18, 2024	- -
Pathogenic, no assertion criteria provided	research	Department of Genetics, Beijing BioBiggen Technology Co., Ltd.	Jun 29, 2022	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2024	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 501 of the PTPN11 protein (p.Arg501Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11992261, 16263833, 18470943, 18562489, 19795160). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40555). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2021	Variant summary: PTPN11 c.1502G>A (p.Arg501Lys) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.1502G>A has been widely reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2002, Limal_2006, Aoki_2008, Noordam_2008, Jefferies_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no 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. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Short stature;C0678230:Epicanthus;C0857379:Abnormal pinna morphology;C1842876:Depressed nasal ridge;C1849367:Wide nasal bridge;C4049796:Abnormal cardiovascular system morphology;C4551563:Microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 13, 2021

ACMG categories: PM1,PM2,PP3,PP4,PP5 -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 26, 2016

The p.Arg501Lys variant in PTPN11 has been reported in >10 individuals with the clinical features of Noonan syndrome and segregated with disease in 1 affected r elative (Tartaglia 2002, Limal 2006, Noordam 2008, Jefferies 2010, LMM unpublish ed data). It has not been identified in large population studies. In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon presence in multiple affected indivi duals, segregation studies, and absence in the general population. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2021

The c.1502G>A (p.R501K) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a G to A substitution at nucleotide position 1502, causing the arginine (R) at amino acid position 501 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple patients with Noonan syndrome (Tartaglia, 2002; Limal, 2006; Noordam, 2008; Jefferies, 2010; Moniez, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PS4_Moderate+PS2_Supporting+PM2_Supporting+PP2+PP3+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.8	.;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.97		Gain of methylation at R501 (P = 0.0126);.;.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507543; hg19: chr12-112926882; COSMIC: COSV61007695; COSMIC: COSV61007695;