12-112450385-G-C

Position:

• chr12-112450385-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4 PS2 PM2 PP3 PP2 PM1

This summary comes from the ClinGen Evidence Repository: The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID:12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hématologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hématologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID:26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID:29493581). PTPN11 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). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261565/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• 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 14 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.
• PM1: 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/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.205G>C	p.Glu69Gln	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.205G>C	p.Glu69Gln	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.205G>C	p.Glu69Gln	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 15928039, 24803665, 12634870, 23624134, 23321623, 26817465, 15001945, 31560489, 32164556, 31130284, 34643321, 36566191, 35979676, 11992261, 9491886, 16053901, 29493581) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2018	- -

RASopathy Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 69 of the PTPN11 protein (p.Glu69Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12634870, 15001945, 20186801, 23321623, 23624134, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40498). 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%. This variant disrupts the p.Glu69 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been observed in individuals with PTPN11-related conditions (PMID: 19077116, 20186801, 20578946), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Dec 05, 2019	The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID: 12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hematologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hematologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID: 26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID: 29493581). PTPN11 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). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2020	Variant summary: PTPN11 c.205G>C (p.Glu69Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251636 control chromosomes (gnomAD and publication data). c.205G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome including one individual determined as de novo (Musante_2003, Zenker_2004, Pierpont_2010, Croonen_2013, Atik_2016, Chinton_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014), including one expert panel (ClinGen RASopathy Variant Curation Expert Panel), cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP2+PP3+PS4+PM6_Strong+PM1 -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2016

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

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2018

The p.E69Q pathogenic mutation (also known as c.205G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 205. The glutamic acid at codon 69 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with Noonan syndrome, including at least one case reported to be de novo (Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Bertelloni S et al. Hormones (Athens), 2013 Jan-Mar;12:86-92; Croonen EA et al. Eur. J. Hum. Genet., 2013 Sep;21:936-42; izmárová M et al. Ann. Hum. Genet., 2016 Jan;80:50-62; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.77
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.7	L;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D;D;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.047	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.80
MutPred		0.86		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.97
MPC		1.7
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.69

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: rs397507511; hg19: chr12-112888189; COSMIC: COSV61009351; COSMIC: COSV61009351;