12-112450359-G-C

Position:

• chr12-112450359-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.179G>C​(p.Gly60Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,998 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G60R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• 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 chr12-112450358-G-C 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, 0.972
• PP5: Variant 12-112450359-G-C is Pathogenic according to our data. Variant chr12-112450359-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450359-G-C is described in Lovd as [Likely_pathogenic]. Variant chr12-112450359-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.179G>C	p.Gly60Ala	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.179G>C	p.Gly60Ala	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.179G>C	p.Gly60Ala	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460998 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726848

Gnomad4 AFR exome AF: 0.00

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 21533187, 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0701 - Many other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many alternative missense changes have been reported in multiple individuals with Noonan syndrome 1 (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the well reported pathogenic variants causes Noonan syndrome (ClinVar, PMID: 32164556). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jun 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.179G>Cp.Gly60Ala has been reported in heterozygous state in individuals affected with Noonan syndrome Athota JP, et. al., 2020. Experimental studies indicates that this variant is expected to disrupt PTPN11 function Tartaglia M, et. al.,2002. The p.Gly60Ala variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The amino acid change p.Gly60Ala in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 60 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040493 ) and different missense changes at the same codon (p.Gly60Arg, p.Gly60Asp, p.Gly60Cys, p.Gly60Ser, p.Gly60Val/ ClinVar ID: VCV000040490, VCV000041442, VCV000055797, VCV000372590, VCV000987743) 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:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	Reported in unrelated individuals with JMML in published literature (Loh et al., 2004; Kratz et al., 2005); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21407260, 16643459, 17020470, 24803665, 29493581, 16053901, 9491886, 11992261, 8328949, 24039098, 18562489, 16263833, 14644997, 18328949, 27521173, 17053061, 26817465, 17546245, 30417923, 28607217, 28328117, 26918529, 31560489, 32164556, 15928039, 34643321, 33318624, 32737134) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PTPN11: PM1, PM2, PM5, PS4:Moderate, PP3, PS2:Supporting -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2024	Variant summary: PTPN11 c.179G>C (p.Gly60Ala) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) 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 251192 control chromosomes (gnomAD). c.179G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2002, 2006, Bertola_2006, Ferfeira_2007, Mutesa_2008). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.178G>A, p.Gly60Ser), supporting the critical relevance of codon 60 to PTPN11 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 15385933, 14644997, 12717436, 16358218, 17020470, 17546245, 18328949, 11992261, 25097206, 19047918, 19179468, 17972951, 15710330, 25395418, 27276561, 27069254, 32561839). ClinVar contains an entry for this variant (Variation ID: 40493). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 60 of the PTPN11 protein (p.Gly60Ala). 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: 11992261, 16643459, 17020470, 18328949, 24039098, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40493). 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. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 09, 2015

The p.Gly60Ala variant has been reported in >20 individuals with clinical featur es of Noonan syndrome (Tartaglia 2002, Binder 2005, Bertola 2006, Limal 2006, Ta rtaglia 2006, Roti 2006, Mutesa 2008, Noordam 2008, Jongmans 2011, Ross 2014, LM M unpublished data) but not identified in large population studies. This variant occurred de novo in at least one of the affected individuals (Roti 2006). In ad dition, this variant has been reported in two individuals with clinical features of Noonan syndrome and a central nervous system tumor (neuroblastoma, Mutesa 20 08; dysembryoplastic neuroepithelia tumor, Jongmans 2011) and as a somatic chang e in AML (Loh 2004). In summary, this variant meets our criteria to be classifie d as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals, de novo occurrence, and absence from control s. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2017

The p.G60A pathogenic mutation (also known as c.179G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 179. The glycine at codon 60 is replaced by alanine, an amino acid with similar properties. This mutation was in multiple individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Bertola DR et al. Genet. Test., 2006;10:186-91; Jongmans MC et al. Eur. J. Hum. Genet., 2011 Aug;19:870-4; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21). In addition, this variant is located in the NSH2 domain, which interacts with the PTP domain to regulate switching of the resulting protein between its inactive and active conformations (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M;.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.1	D;D;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.014	D;D;.;.
Sift4G	Uncertain	0.0030	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.88
MutPred		0.88		Loss of stability (P = 0.0578);Loss of stability (P = 0.0578);Loss of stability (P = 0.0578);Loss of stability (P = 0.0578);
MVP		0.97
MPC		2.0
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.72

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: rs397507509; hg19: chr12-112888163; COSMIC: COSV61006397; COSMIC: COSV61006397;