chr12-112488444-G-A

Position:

• chr12-112488444-G-A

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.1381G>A​(p.Ala461Thr) variant causes a missense, splice region 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. 15/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A461S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense, splice_region
• Scores: Splicing: ADA: 0.9800
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.48

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 (HGNC:):

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 chr12-112488444-G-T 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). 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, 0.992
• PP5: Variant 12-112488444-G-A is Pathogenic according to our data. Variant chr12-112488444-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112488444-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1381G>A	p.Ala461Thr	missense_variant, splice_region_variant	12/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1393G>A	p.Ala465Thr	missense_variant, splice_region_variant	12/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1378G>A	p.Ala460Thr	missense_variant, splice_region_variant	12/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1390G>A	p.Ala464Thr	missense_variant, splice_region_variant	12/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1381G>A	p.Ala461Thr	missense_variant, splice_region_variant	12/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1393G>A	p.Ala465Thr	missense_variant, splice_region_variant	12/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.394G>A	p.Ala132Thr	missense_variant, splice_region_variant	4/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LEOPARD syndrome 1 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -

Noonan syndrome 1 Pathogenic:2

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) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene associated with Noonan syndrome are known to have variable expressivity (GeneReviews). 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (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) 0601 - Variant is located in the well-established functional protein-tyrosine phosphatase (PTP) domain. The alanine residue at position 461, is an active site involved in substrate binding in the PTP domain (UniProt, PMID 24935154). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Noonan syndrome and LEOPARD syndrome, several with de novo inheritance (PMID: 23799168, PMID: 15470362, PMID: 21784453, PMID: 22190897, VCGS, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 02, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2022	Published functional studies demonstrate this variant results in either a dramatic reduction of catalytic activity or complete catalytic inactivity (Yu et al., 2014; Kontaridis et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24935154, 20493809, 24718990, 16377799, 25937001, 24803665, 15470362, 28483241, 15389709, 23799168, 30055033, 30050098, 29907801, 32573669, 26918529, 24077912) -
Pathogenic, criteria provided, single submitter	clinical testing	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	Feb 02, 2022	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2020	Variant summary: PTPN11 c.1381G>A (p.Ala461Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251372 control chromosomes (gnomAD and publication data). c.1381G>A has been reported in the literature in multiple individuals with clinical features of NSRD, including de novo occurrences (Ypshida_2004, Chu_2011, Lee_2011, Digilio_2012, Ezquieta_2012, Croonen_2013, Leach_2019). These data indicate that the variant is very likely to be associated with disease. Functional studies report the variant effect results in catalytic inactivity and was shown to strongly inhibiting EGF-evoked Erk activation in a dominant-negative manner (Kontaridis_2006, Yu_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 20493809, 24718990, 24935154). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. ClinVar contains an entry for this variant (Variation ID: 13342). This missense change has been observed in individual(s) with LEOPARD syndrome (PMID: 15389709, 15470362, 23799168). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 461 of the PTPN11 protein (p.Ala461Thr). -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 07, 2018

The PTPN11 c.1381G>A; p.Ala461Thr variant (rs121918468) is reported in the literature in multiple individuals affected with LEOPARD syndrome and symptoms of Noonan syndrome (Chu 2013, Sarkozy 2004, Yoshida 2004). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13342) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in the protein tyrosine signature motif involved in phosphate binding (Kontaridis 2006, Sarkozy 2004, Yu 2014), and other variants associated with LEOPARD syndrome, including another variant at the same codon, p.Ala461Ser, have also been described in this domain (Yoshida 2004, Osawa 2009). Biochemical characterization of p.Ala461Thr PTPN11 variant protein shows severely reduced phosphatase activity (Kontaridis 2006, Yu 2014). This variant also fails to rescue developmental defects of a zebrafish shp2 (PTPN11) morphant to the same extent as wildtype (Bonetti 2014, Stewart 2010). The alanine at codon 461 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ala461Thr variant is considered pathogenic. REFERENCES Bonetti M et al. Noonan and LEOPARD syndrome Shp2 variants induce heart displacement defects in zebrafish. Development. 2014 May;141(9):1961-70. Chu HS et al. Syndromic Hearing Loss in Association with PTPN11-Related Disorder: The Experience of Cochlear Implantation in a Child with LEOPARD Syndrome. Clin Exp Otorhinolaryngol. 2013 Jun;6(2):99-102. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. Osawa R et al. A novel PTPN11 missense mutation in a patient with LEOPARD syndrome. Br J Dermatol. 2009 Nov;161(5):1202-4. Sarkozy A et al. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004 Dec;12(12):1069-72. Stewart RA et al. Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. Dev Cell. 2010 May 18;18(5):750-62. Yoshida R et al. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet A. 2004 Nov 1;130A(4):432-4. Yu ZH et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014 Jul 1;53(25):4136-51. -

Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

The p.Ala461Thr variant in PTPN11 has been previously identified in 10 individua ls with clinical features of a LEOPARD (Sarkozy 2004, Yoshida 2004, Digilio 2010 , Chu 2013, LMM unpublished data) and occurred de novo in 3 of these individuals (Sarkozy 2004, Chu 2013, LMM unpublished data). It was absent from large popula tion studies. Furthermore, in-vitro and in-vivo functional studies suggest this variant has a dominant negative effect, which is an established pathogenic mecha nism in LEOPARD (Kontaridis 2006, Stewart 2010, Yu 2014). In summary, this varia nt meets our criteria to be classified as pathogenic for a LEOPARD (http://www.p artners.org/personalizedmedicine/LMM). -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2023

The PTPN11 c.1381G>A variant is predicted to result in the amino acid substitution p.Ala461Thr. This variant has been documented in at least four individuals with Noonan syndrome with multiple lentigines (Sarkozy et al. 2004. PubMed ID: 15470362; Yoshida et al. 2004. PubMed ID: 15389709; Chu et al. 2013. PubMed ID: 23799168; van Nierop et al. 2017. PubMed ID: 28483241) and was de novo in at least two of these individuals (Sarkozy et al. 2004. PubMed ID: 15470362; Chu et al. 2013. PubMed ID: 23799168). Additionally, this variant was found in three prenatal cases with cystic hygroma with or without congenital heart defects (Hakami et al. 2016. PubMed ID: 26918529; Table S2 - Leach et al. 2019. PubMed ID: 29907801). Two studies found the p.Ala461Thr variant imparts a dominant-negative effect resulting in a reduction in RAS pathway signaling (Kontaridis et al. 2006. PubMed ID: 16377799; Stewart et al. 2010. PubMed ID: 20493809). Consistent with the previous studies, another found the variant does result in lower catalytic activity; however, the activation of PTPN11 was prolonged (Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13342/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.98		Loss of helix (P = 0.1299);.;.;
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.89
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: rs121918468; hg19: chr12-112926248; COSMIC: COSV61005148; COSMIC: COSV61005148;