rs397507539

Positions:

• chr12-112489047-C-A
• chr12-112489047-C-G
• chr12-112489047-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1471C>A​(p.Pro491Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,676 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P491A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• 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 17 ACMG points.

• PM1: In a hotspot region, there are 2 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 chr12-112489048-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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). GenCC has associacion of 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, 0.884
• PP5: Variant 12-112489047-C-A is Pathogenic according to our data. Variant chr12-112489047-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489047-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1471C>A	p.Pro491Thr	missense_variant	13/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1483C>A	p.Pro495Thr	missense_variant	13/16
PTPN11	NM_001374625.1	c.1468C>A	p.Pro490Thr	missense_variant	13/16
PTPN11	XM_011538613.3	c.1480C>A	p.Pro494Thr	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1471C>A	p.Pro491Thr	missense_variant	13/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727144

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22781091, 21526175, 26582918, 22465605, 27535533) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 28, 2020	The PTPN11 c.1471C>A (p.Pro491Thr) variant is a missense variant that has been reported in at least one individual affected with Noonan syndrome who inherited the variant from their affected father (Ezquieta et al. 2012). Other missense changes at the Pro491 residue, Pro491Ser, Pro491Leu and Pro491His have been reported to be pathogenic and have been found in individuals with Noonan syndrome (Binder et al. 2005; Ezquieta et al. 2012; Čizmárová et al. 2016). The p.Pro491Thr variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Based on the collective evidence, de novo origin of the variant and application of the ACMG criteria, the p.Pro491Thr variant is classified as pathogenic for Noonan syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 21, 2013	The Pro491Thr variant has been reported in at least 6 individuals with clinical features of Noonan syndrome (Chan 2006, Carcavilla Urqui 2006, Ezquieta 2012, LM M unpublished data). In one of these individuals, the variant was inherited fro m an affected mother (Chan 2006). At our laboratory, we have identified this var iant in 3 individuals with clinical features of Noonan syndrome and the variant was also identified in at least one affected family member in each case. We have also tested several additional individuals with clinical features of Noonan spe ctrum disorders who had other amino acid changes at this position (Pro491Leu, Pr o491Ser, Pro491His). In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 11, 2015	- -

Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Jun 06, 2019	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 19, 2018	Two different missense substitutions at this codon (p.Pro491Ser and p.Pro491Leu) have been determined to be pathogenic (PMID: 22465605, 22781091). This suggests that the proline residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline with threonine at codon 491 of the PTPN11 protein (p.Pro491Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 21526175, 22465605; http://www.hkjpaed.org/details.asp?id=581&show=1234). ClinVar contains an entry for this variant (Variation ID: 40549). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2021	Variant summary: PTPN11 c.1471C>A (p.Pro491Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Other missense variants located at this codon have been reported in patients with Noonan syndrome within the HGMD database supporting the notion of critical functional relevance of this Proline residue. The variant was absent in 251480 control chromosomes. c.1471C>A has been reported in the literature in at-least one well genotyped Spanish individual affected with Noonan Syndrome (example, Ezquieta_2012) and in another individual with Noonan syndrome in whom the possibility of a cohort/patient overlap with the earlier ascertainment cannot be excluded within the context of this evaluation (Gomez-Carballa_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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=4)/likely pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical patients, confirmed de-novo origin and/or a functional study is identified, the variant was classified as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2024

The c.1471C>A (p.P491T) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a C to A substitution at nucleotide position 1471, causing the proline (P) at amino acid position 491 to be replaced by a threonine (T)._x000D_ _x000D_ for PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with PTPN11-related RASopathy (Chan, 2006; Gómez-Carballa, 2011; Ezquieta, 2012; Valentino, 2021; Carcavilla, 2023). _x000D_ _x000D_ Three other alterations at the same codon, c.1472C>A (p.P491H), c.1471C>T (p.P491S), and c.1472C>T (p.P491L), have been described in individuals with clinical features consistent with PTPN11-related RASopathy (Bertola, 2006; DECIPHER v.9.32; Ambry internal data). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
CardioboostCm	Uncertain	0.89
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.045	D;.;.
Sift4G	Benign	0.43	T;T;T
Polyphen		0.61	P;.;.
Vest4		0.94
MutPred		0.77		Gain of MoRF binding (P = 0.0938);.;.;
MVP		0.98
MPC		2.0
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95

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: rs397507539; hg19: chr12-112926851;