rs397507517

Positions:

• chr12-112450497-A-C
• chr12-112450497-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.317A>C​(p.Asp106Ala) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.32

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.957
• PP5: Variant 12-112450497-A-C is Pathogenic according to our data. Variant chr12-112450497-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 40506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450497-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.317A>C	p.Asp106Ala	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.317A>C	p.Asp106Ala	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.317A>C	p.Asp106Ala	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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18286234). 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: 40506). This missense change has been observed in individuals with Noonan syndrome (PMID: 12717436, 18470943). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 106 of the PTPN11 protein (p.Asp106Ala). -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 26, 2021	The inherited heterozygous missense variant c.317A>C (p.Asp106Ala) identified in exon 3 (of 16) of the PTPN11 gene is a known pathogenic variant that has been reported in multiple unrelated individuals affected with Noonan spectrum disorders (PMID: 32164556, 17339163, 29907801, 19077116,16990350, 21204800, 11992261). This variant is reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID:40506). This variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. In vitro functional analyses suggest that this variant (located in the linker region between the NSH2 and C-SH2 domains of the PTPN11 protein) results in an increased activity due to misfolding of the inter-SH2 domain linker (PMID:15987685, 18286234). Based on the available evidence, the inherited heterozygous c.317A>C (p.Asp106Ala) variant identified in the PTPN11 gene is reported as Pathogenic. -

Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP2+PS3+PS4 -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 09, 2020	ACMG codes:PS3; PS4; PM1; PM2; PP2; PP3 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	Common missense variant in PTPN11, observed in 2-5% of patients with Noonan syndrome with or without multiple giant-cell lesions (PMID: 18470943, 12717436, 17020470, 16358218, 17339163, 16990350, 19077116, 21204800, 33318624, 11992261); Not observed at significant frequency in large population cohorts (gnomAD); Located in the linker region between the NSH2 and C-SH2 domains of the SHP-2 protein encoded by PTPN11 (PMID: 15987685); 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21204800, 22848035, 28607217, 22420426, 19737548, 16208280, 23584145, 18854871, 31292302, 34930662, 24803665, 19835954, 19077116, 16990350, 17339163, 16358218, 12960218, 23624134, 24451042, 21590266, 25862627, 12717436, 16053901, 17020470, 22488759, 26124496, 30050098, 30410095, 29907801, 32164556, 18286234, 33318624, 29493581, 18470943, 11992261, 36588761, 15987685, 16987887) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2020	The PTPN11 c.317A>C; p.Asp106Ala variant (rs397507517) is reported in the literature in multiple individuals affected with Noonan syndrome (Bertelloni 2013, Hung 2007, Leach 2019, Pierpont 2009, Shaw 2007, Stevenson 2011, Tartaglia 2002). This variant is also reported in ClinVar (Variation ID: 40506), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 106 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show hyperactivation upon peptide addition (Keilhack 2005). Additionally, another variant at this codon (c.317A>G; p.Asp106Gly) has been reported in individuals with Noonan syndrome (Bertelloni 2013). Based on available information, the p.Asp106Ala variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. Hung CS et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Leach NT et al. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019 Feb;21(2):417-425. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. Shaw AC et al. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32. Stevenson DA et al. Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet. 2011 Dec;80(6):566-73. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 20, 2019	The p.Asp106Ala variant in PTPN11 has been reported in >10 individuals with Noonan syndrome-related disorders and non-immune hydrops fetalis. It segregated with disease in 2 affected individuals from 1 family (Tartaglia 2002, Bertola 2006, Tartaglia 2006, Hung 2007, Shaw 2007, Pierpont 2009, Stevenson 2010, Leach 2019, Sparks 2019). It has additionally been observed at the Laboratory for Molecular Medicine in 7 individuals, 5 with Noonan syndrome-like features and 1 with pulmonary stenosis. The variant was found to be de novo in 1 case (LMM Data). This variant was also observed de novo in a patient with Noonan syndrome tested by GeneDx (Clinvar Variation ID: 40506, Accession: SCV000057388.14). It was absent from large population studies. In vitro functional studies provide some evidence that the p.Asp106Ala variant may impact protein function (Keilhack 2005, Chan 2008, Lee 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome-related disorders. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2, PP3, PS3_Supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 25, 2015	- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;M;.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D;D;.;.
REVEL	Pathogenic	0.94
Sift	Benign	0.075	T;T;.;.
Sift4G	Uncertain	0.015	D;D;.;D
Polyphen		0.98	D;P;.;.
Vest4		0.85
MutPred		0.82		Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);
MVP		0.96
MPC		2.1
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.74

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: rs397507517; hg19: chr12-112888301; COSMIC: COSV100692441; COSMIC: COSV100692441;