12-112450361-G-C

Position:

• chr12-112450361-G-C

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.181G>C​(p.Asp61His) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.99

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 SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) 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 chr12-112450362-A-G is described in Lovd as [Likely_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, 0.971
• PP5: Variant 12-112450361-G-C is Pathogenic according to our data. Variant chr12-112450361-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450361-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.181G>C	p.Asp61His	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.181G>C	p.Asp61His	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.181G>C	p.Asp61His	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Aug 27, 2024

- -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

The PTPN11 c.181G>C variant is predicted to result in the amino acid substitution p.Asp61His. This variant has been reported in multiple unrelated individuals with Noonan syndrome, and this variant was occurred to be de novo in some of them (see for example, Houweling et al. 2010. PubMed ID: 20112233; Strullu et al. 2014. PubMed ID: 25097206; Leach et al. 2018. PubMed ID: 29907801). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 15, 2018

The D61H pathogenic variant in the PTPN11 gene has been reported previously as de novo and in association with Noonan syndrome (Houweling et al., 2010). This variant is not observed in large population cohorts (Lek et al., 2016). D61H is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. It lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (D61N/G/A) and nearby residues (I56V, N58H/D/K, T59A, G60C/S/A, Y62D/N/C, Y63C) have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant to be pathogenic. -

Noonan syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 06, 2016

Variant summary: The PTPN11 c.181G>C (p.Asp61His) variant involves the alteration of a conserved nucleotide located within the interface of the amino-terminal SH2 (N-SH2) and catalytic (PTP) domains. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121392 control chromosomes while it was reported in several Noonan Syndrome patients. In one of these patients, the variant proved to be de novo, strongly supporting a pathogenic impact. Furthermore, mutations affecting the same codon Asp61Ala, Asp61Asn, Asp61Gly are listed in databases (HGMD, ClinVar) as pathogenic indicating the variant to be located in a mutational hotspot and the clinical relevance of the Asp61 residue. Considering all evidence, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2020

The p.D61H pathogenic mutation (also known as c.181G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 181. The aspartic acid at codon 61 is replaced by histidine, an amino acid with similar properties. This mutation occurred de novo in a fetus with an increased nuchal translucency (NT), jugular lymphatic sacs, pericardial effusion, atrioventricular septal defect, dilated renal pelvices, short femurs, webbing of neck, ocular hypertelorism, and posteriorly rotated low set ears (Houweling AC et al. Prenat. Diagn., 2010 Mar;30:284-6). It was also identified in tow additional fetuses with increased NTs; however, details were limited (Leach NT et al. Genet. Med., 2019 02;21:417-425). This mutation was also identified in two infants with Noonan syndrome and juvenile myelomonocytic leukemia (Strullu M et al. J. Med. Genet., 2014 Oct;51:689-97). A known disease-causing mutation, p.D61N, has also been described in the same codon in multiple individuals with confirmed or suspected Noonan syndrome, including multiple de novo cases (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ferreira LV et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5156-60; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Derbent M et al. Am. J. Med. Genet. A, 2010 Nov;152A:2768-74; Lee BH et al. J. Pediatr., 2011 Dec;159:1029-35; Pasmant E et al. Am. J. Med. Genet. A, 2012 Sep;158A:2290-1; Strullu M et al. J. Med. Genet., 2014 Oct;51:689-97; van Trier DC et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jun;79:874-8; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Joyce S et al. Eur. J. Hum. Genet., 2016 May;24:690-6). Based on the supporting evidence, the p.D61H alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.88
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;L;.;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.6	D;D;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.90		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.79

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: rs397507510; hg19: chr12-112888165; COSMIC: COSV61006072; COSMIC: COSV61006072;