rs397507523

Positions:

• chr12-112472954-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.767A>G​(p.Gln256Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,928 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.95

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.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) in NM_002834.5
• 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, 0.885
• PP5: Variant 12-112472954-A-G is Pathogenic according to our data. Variant chr12-112472954-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112472954-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.767A>G	p.Gln256Arg	missense_variant	7/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.767A>G	p.Gln256Arg	missense_variant	7/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.767A>G	p.Gln256Arg	missense_variant	7/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458928 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725930

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function 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, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Parents might only be diagnosed when they have an affected child (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Noonan syndrome (PMIDs: 12634870, 31562133, 35979676). In addition, it has been regarded as likely pathogenic and pathogenic by several clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 20, 2023	The PTPN11 c.767A>G (p.Gln256Arg) missense variant has been identified in a heterozygous state in individuals with a phenotype consistent with Noonan syndrome (PMID: 12634870; 15985475; 24451042; 29907801; 32164556; 35979676). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the p.Gln256Arg variant may impact the gene or gene product. This variant has been shown to segregate with disease in this family and in a family in the literature (PMID: 35979676). Based on the available evidence, the c.767A>G (p.Gln256Arg) variant is classified as pathogenic for Noonan syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Oct 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 31, 2023	The PTPN11 c.767A>G variant is classified as a PATHOGENIC variant (PS4, PM1, PM2, PM6_supporting, PP3) The variant is a single nucleotide change in exon 7/16 of the PTPN11 gene, which is predicted to change the amino acid glutamine at position 256 in the protein to arginine. The variant is located in a mutational hot spot: PTP protein domain, of the PTPN11 gene (PM1). The variant has been reported multiple times in unrelated individuals affected with Noonan syndrome in the heterozygous state. The variant was assumed de novo in the affected individuals; but in the latter report the variant was inherited from the affected father (PMID: 12634870, 32164556, 1635821, 24451042) (PS4) (PM6_supporting). The variant has been reported in dbSNP (rs397507523) but is absent from population databases (PM2). The variant has been reported in ClinVar (Variation ID: 40518) as pathogenic/ likely pathogenic by multiple diagnostic laboratories. The variant has been reported in HGMD (Accession no.: CM030495) as disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2022	Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); 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: 12634870, 24803665, 16358218, 22681964, 15001945, 18470943, 15985475, 32164556, 30050098, 29907801, 24451042, 11992261, 9491886, 16053901, 29493581) -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln256 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been observed in individuals with PTPN11-related conditions (PMID: 15985475), which suggests that this may be a clinically significant amino acid residue. 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: 40518). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 12634870, 16358218, 24451042; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 256 of the PTPN11 protein (p.Gln256Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2019	Variant summary: PTPN11 c.767A>G (p.Gln256Arg) results in a conservative amino acid change located in the PTP type protein phosphatase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249002 control chromosomes (gnomAD and publications). c.767A>G has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Musante_2003, Tartaglia_2006, Ezquieta_2012, Lepri_2014). These data indicate that the variant is likely to be associated with disease. Five ClinVar submissions (evaluation after 2014) cite the variant three times as pathogenic and twice as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 20, 2017

- -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 29, 2014

The p.Gln256Arg variant in PTPN11 has been reported in 8 individuals with clinic al features Noonan syndrome or LEOPARD syndrome (Musante 2003, Tartaglia 2006, L epri 2014, LMM unpublished data) but has not been identified in large population studies (ExAC, http://exac.broadinstitute.org; dbSNP rs397507523). The glutamin e (Gln) at position 256 is highly conserved in mammals and across evolutionarily distant species, and disease-causing variants in PTPN11 are typically missense. In summary, the p.Gln256Arg variant meets our criteria to be classified as path ogenic for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner based upon recurrence in multiple affected individuals, extremely low frequency in the general population, high evolutionary conservation, and consistent varian t type. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

The p.Q256R variant (also known as c.767A>G), located in coding exon 7 of the PTPN11 gene, results from an A to G substitution at nucleotide position 767. The glutamine at codon 256 is replaced by arginine, an amino acid with highly similar properties. This alteration was first described in a patient with a clinical diagnosis of Noonan syndrome (Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6) and has subsequently been reported in multiple individuals with a suspected or confirmed diagnosis; in the latter report the alteration was paternally inherited (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Lepri FR et al. BMC Med. Genet., 2014 Jan;15:14). Functional studies suggest missense changes involving Q256 affect substrate specificity (Martinelli S et al. Hum Mutat, 2020 Jun;41:1171-1182). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.014	D;T;.
Sift4G	Benign	0.095	T;T;T
Polyphen		0.062	B;B;.
Vest4		0.80
MutPred		0.76		Loss of ubiquitination at K260 (P = 0.0387);Loss of ubiquitination at K260 (P = 0.0387);Loss of ubiquitination at K260 (P = 0.0387);
MVP		1.0
MPC		1.5
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.52

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: rs397507523; hg19: chr12-112910758;