rs397507504

Variant names:

• chr12-112450346-A-G
• rs397507504
• NM_002834.5:c.166A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-112450346-A-G
• chr12-112450346-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3 PP2 PS2 PS4

This summary comes from the ClinGen Evidence Repository: The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4, PM2, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180973/MONDO:0021060/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.31

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.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.166A>G	p.Ile56Val	missense_variant	Exon 3 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.166A>G	p.Ile56Val	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.166A>G	p.Ile56Val	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460668 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726714

Gnomad4 AFR exome AF: 0.0000299

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 1 Pathogenic:4

Nov 15, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.166A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid isoleucine at position 56 in the protein to valine. This variant is absent from population databases (PM2), but has been reported at least 4 times in the literature in patients with a clinical presentation of Noonan syndrome or RASopathy (PS4_Moderate). A different pathogenic missense change, p.Ile56Thr, has been reported before at the same amino acid position (PM5). This variant has been identified as a de novo variant in at least two affected patients with no family history of this condition (Li et al, 2020 PMID: 32410215; Brunet et al, 2021 PMID 33619735) (PS2). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40485). The variant has been reported in the HGMD database: CM161482. Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Jun 06, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.90 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in the same amino acid change (ClinVar ID: VCV000040485 / PMID: 26817465) and a different missense change at the same codon (p.Ile56Thr / ClinVar ID: VCV000477669) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Aug 17, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26817465, 29907801, 32410215, 30050098, 29493581, 36555586, 33619735) -

RASopathy Pathogenic:2

Nov 19, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: PTPN11 c.166A>G (p.Ile56Val) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 control chromosomes (gnomAD). The variant, c.166A>G, has been reported in the literature and by clinical laboratories in multiple individuals affected with features of Noonan Syndrome and Related Conditions (Smith_2009, Atik_2016, Leach_2018, ClinVar database). Additionally, one reportedly de novo occurrence was observed by a clinical laboratory (ClinVar database). In addition, this variant was identified at our laboratory in one patient with pulmonary stenosis and ASD. These data indicate that the variant is very likely to be associated with disease. Several mutations in neighboring codons (N58K, N58H, and N58D) have been published in association with Noonan Syndrome, emphasizing the functional importance of this residue and/or SH2 region.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as likely pathogenic (3x) and pathogenic (2x). Based on the evidence outlined above, the variant was re-classified as pathogenic. -

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the PTPN11 protein (p.Ile56Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 26817465; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40485). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

PTPN11-related disorder Pathogenic:1

Dec 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.166A>G variant is predicted to result in the amino acid substitution p.Ile56Val. This variant has been reported in multiple individuals with Noonan syndrome and in some of these cases was determined to have arisen de novo (Atik et al. 2016. PubMed ID: 26817465; Li et al. 2020. PubMed ID: 32410215; Brunet et al. 2021. PubMed ID: 33619735; Table S3 in Leach et al. 2019. PubMed ID: 29907801). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel on the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/variation/40485). This variant is interpreted as pathogenic. -

Noonan syndrome Pathogenic:1

Feb 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

May 10, 2019

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4, PM2, PP3, PP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.32
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;.;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;L;.;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.90	N;N;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Benign	0.14	T;T;.;T
Polyphen		0.98	D;P;.;.
Vest4		0.78
MutPred		0.69		Gain of methylation at K55 (P = 0.045);Gain of methylation at K55 (P = 0.045);Gain of methylation at K55 (P = 0.045);Gain of methylation at K55 (P = 0.045);
MVP		0.89
MPC		1.6
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.61

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: rs397507504; hg19: chr12-112888150;