12-112489083-G-C

Position:

chr12-112489083-G-C

Variant summary

Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The ENST00000351677.7(PTPN11):c.1507G>C(p.Gly503Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G503A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTPN11
ENST00000351677.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.60

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 27 ACMG points.

PS1

Transcript ENST00000351677.7 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 40559

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000351677.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112489084-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40561.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, 0.988

PP5

Variant 12-112489083-G-C is Pathogenic according to our data. Variant chr12-112489083-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489083-G-C is described in Lovd as [Pathogenic]. Variant chr12-112489083-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PTPN11	NM_002834.5 linkuse as main transcript	c.1507G>C	p.Gly503Arg	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2 linkuse as main transcript	c.1519G>C	p.Gly507Arg	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1 linkuse as main transcript	c.1504G>C	p.Gly502Arg	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3 linkuse as main transcript	c.1516G>C	p.Gly506Arg	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.1507G>C	p.Gly503Arg	missense_variant	13/16	1	NM_002834.5	ENSP00000340944	A1	Q06124-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

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:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS1, PM1, PM2, PM5, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040558,VCV000040559,VCV000571101, PMID:12960218,16358218, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040561, PMID:18678287,21407260,23756559, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992, 3CNET: 0.994, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Apr 26, 2022	ACMG categories: PS1,PS4,PM6,PP3,PP4,PP5 -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2022	Reported as a germline variant in patients with features of a Noonan spectrum disorder and myeloproliferative disease or leukemia (including JMML and AML), and in one patient with features of a Noonan spectrum disorder and Hodgkin's lymphoma (Tartgalia et al., 2003; Lo et al., 2008; Bluteau et al., 2018); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19737548, 23334668, 16358218, 24754368, 29703613, 30355677, 30670449, 29037749, 26918529, 18758896, 30417923, 15001945, 22681964, 19077116, 27592337, 15928039, 29146883, 30050098, 29907801, 31560489, 33144682, 29493581, 33683002, 33318624, 34008892, 12960218, 12717436) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2020	PS1, PS4, PM5, PM6, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	The PTPN11 c.1507G>C; p.Gly503Arg variant (rs397507545) is reported in the literature in multiple individuals affected with Noonan syndrome and has been reported de novo in several (Chaves Rabelo 2022, Chinton 2019, Faggetter 2023, Hakami 2016, Matalon 2021, Mathus 2014, Sarkozy 2003). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.992). Based on available information, this variant is considered to be pathogenic. References: Chaves Rabelo N et al. RASopathy Cohort of Patients Enrolled in a Brazilian Reference Center for Rare Diseases: A Novel Familial LZTR1 Variant and Recurrent Mutations. Appl Clin Genet. 2022 Oct 21;15:153-170. PMID: 36304179. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. PMID: 31560489. Faggetter S et al. Hereditary spherocytosis associated with Noonan syndrome mimicking a dyserythropoietic anaemia. Pediatr Blood Cancer. 2023 Apr;70(4):e30121. PMID: 36579772. Hakami F et al. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn. 2016 May;36(5):418-23. PMID: 26918529. Matalon DR et al. Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies. Am J Med Genet A. 2021 May;185(5):1486-1493. PMID: 33683002. Mathur D et al. Twin infant with lymphatic dysplasia diagnosed with Noonan syndrome by molecular genetic testing. Fetal Pediatr Pathol. 2014 Aug;33(4):253-7. PMID: 24754368. Sarkozy A et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003 Sep;40(9):704-8. PMID: 12960218. -

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 503 of the PTPN11 protein (p.Gly503Arg). This variant is present in population databases (rs397507545, gnomAD 0.004%). This missense change has been observed in individuals with Noonan syndrome or Leopard syndrome (PMID: 12717436, 12960218, 16358218, 18758896, 19077116, 19737548, 24754368). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40558). 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 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	Feb 01, 2021	Variant summary: PTPN11 c.1507G>C (p.Gly503Arg) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 252092 control chromosomes. c.1507G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions, including a father and daughter showing co-segregation with disease (e.g. Zenker_2004, Tartaglia_2006, Lo_2008, Pierpont_2009, Mathur_2014, Bessis_2019, Chinton_2019). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2018

The p.Gly503Arg (due to c.1507G>C or c.1507G>A) variant has previously been repo rted >10 individuals with the clinical features of Noonan syndrome, including at least 2 de novo occurrences (Tartaglia 2003, Sarkozy 2003, Zenker 2004, Kratz 2 005, Lo 2008, Ezquieta 2012, LMM data). This variant has also been reported in i ndividuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML), JMM L, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Lo 2008). It ha s not been identified in large population studies. Three other variants involvin g this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as patho genic. Computational prediction tools and conservation analysis suggest that the p.Gly503Arg variant may impact the protein. In summary, this variant meets crit eria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4; PM1; PM2; PM6; PP3. -

PTPN11-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

The PTPN11 c.1507G>C variant is predicted to result in the amino acid substitution p.Gly503Arg. This variant is located in a mutational hotspot region of the PTPN11 gene. It has been repeatedly reported to be causative for Noonan syndrome (Sarkozy et al. 2003. PubMed ID: 12960218; Holmfeldt et al. 2013. PubMed ID: 23334668; Chinton et al. 2019. PubMed ID: 31560489). Additionally, a different variant, 1507G>A, that results in the same amino acid change has been reported as causative for Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218). At PreventionGenetics, we previously detected the variant c.1507G>C in other affected patients. This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Neurodevelopmental disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Feb 24, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2020

The p.G503R pathogenic mutation (also known as c.1507G>C), located in coding exon 13 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1507. The glycine at codon 503 is replaced by arginine, an amino acid with dissimilar properties, and is located in the PTP domain of the PTPN11 protein. This mutation has been reported in multiple individuals with Noonan syndrome, including at least two affected parent-child pairs (Sarkozy A et al. J Med Genet, 2003 Sep;40:704-8; Lo FS et al. Int J Hematol, 2008 Oct;88:287-290; Bessis D et al. Br J Dermatol, 2019 06;180:1438-1448). The same amino acid substitution caused by a different nucleotide change (c.1507G>A) has also been reported in individuals with Noonan syndrome (Tartaglia M et al. Am J Hum Genet, 2006 Feb;78:279-90; Athota JP et al. BMC Med Genet, 2020 03;21:50). There have been reports of a few individuals with p.G503R and Noonan syndrome diagnosed with juvenile myelomonocytic leukemia (JMML) (Strullu M et al. J Med Genet, 2014 Oct;51:689-97; Kratz CP et al. Br J Cancer, 2015 Apr;112:1392-7). In addition, other alterations at the same residue (p.G503A and p.G503E) have also been described in individuals with features of Noonan syndrome (Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Jongmans MC et al. Eur. J. Hum. Genet., 2011 Aug;19:870-4). Based on internal structural analysis, p.G503R is more destabilizing than other nearby pathogenic variants (Hof P et al. Cell, 1998 Feb;92:441-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

.;M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.3

D;.;.

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.93

Gain of MoRF binding (P = 0.0178);.;.;

MVP

0.99

MPC

2.1

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over