rs397509344

chr12-112488445-C-Gchr12-112488445-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_002834.5(PTPN11):c.1382C>G(p.Ala461Gly) 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A461T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr12-112488444-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 40546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 12-112488445-C-G is Pathogenic according to our data. Variant chr12-112488445-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55798.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1382C>G	p.Ala461Gly	missense_variant, splice_region_variant	12/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1394C>G	p.Ala465Gly	missense_variant, splice_region_variant	12/16
PTPN11	NM_001374625.1	c.1379C>G	p.Ala460Gly	missense_variant, splice_region_variant	12/16
PTPN11	XM_011538613.3	c.1391C>G	p.Ala464Gly	missense_variant, splice_region_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1382C>G	p.Ala461Gly	missense_variant, splice_region_variant	12/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2016	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala461Gly variant in PTPN11 has not been previously reported in individuals with clinical features of a RASopathy and is absent from large population studies. An additio nal pathogenic amino acid change at this position (p.Ala461Thr) has been reporte d in individuals with clinical features of LEOPARD syndrome (Sarkozy 2004, Yoshi da 2004, Digilio 2011) suggesting that a change at this position may not be tole rated. Computational prediction tools and conservation analysis do not provide s trong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala4 61Gly variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2021	Variant summary: PTPN11 c.1382C>G (p.Ala461Gly) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase (IPR003595) active binding site catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251172 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although c.1382C>G has been reported as a somatic variant in patients with myeloid malignancies such as AML (example, Papaemmanuil_2016, Alfayez_2021), to our knowledge, no occurrence of c.1382C>G in individuals affected with Noonan Syndrome and Related Conditions has been reported. At least one publication reports experimental evidence evaluating an impact on protein function of another alteration at codon 461 (p.Ala461Thr) that has been observed in patients with Leopard syndrome (Kontaridis_2006). This publication reported p.Ala461Thr as a catalytically inactive dominant-negative mutation, however, it does not allow convincing conclusions about the variant effect of p.Ala461Gly. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

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PTPN11-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2023

The PTPN11 c.1382C>G variant is predicted to result in the amino acid substitution p.Ala461Gly. This variant has been reported in an individual with clinical features consistent with Noonan syndrome (Table S2, Saini et al 2022. PubMed ID: 35587316) and as a somatic variant in individuals with myeloid malignancies (Table S5, Papaemmanuil et al. 2016. PubMed ID: 27276561). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, two additional missense variants impacting the same amino acid (p.Ala461Ser, p.Ala461Thr) have been reported in individuals with Noonan syndrome and Noonan syndrome with multiple lentigines (Sarkozy et al. 2004. PubMed ID: 15470362; Yoshida and Ogata. 2008. PubMed ID: 24790373; Osawa et al. 2009. PubMed ID: 19659470). Additionally, in vitro and in vivo experimental studies of the p.Ala461Thr variant suggest a dominant-negative impact on protein function (Kontaridis et al. 2006. PubMed ID: 16377799; Stewart et al. 2010. PubMed ID: 20493809; Bonetti et al. 2014. PubMed ID: 24718990). Therefore, based on the available evidence, the p.Ala461Gly variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.94		Gain of glycosylation at S460 (P = 0.0448);.;.;
MVP		0.94
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		0.92
gMVP		0.92

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

Other links and lift over

dbSNP: rs397509344; hg19: chr12-112926249; COSMIC: COSV61005273; COSMIC: COSV61005273;