12-112450408-G-C

Variant names:

• chr12-112450408-G-C
• rs397507514
• NM_002834.5:c.228G>C

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.228G>C​(p.Glu76Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,524 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.04

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 21 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 8) in uniprot entity PTN11_HUMAN there are 16 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 chr12-112450407-A-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.933
• PP5: Variant 12-112450408-G-C is Pathogenic according to our data. Variant chr12-112450408-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450408-G-C is described in Lovd as [Likely_pathogenic]. Variant chr12-112450408-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.228G>C	p.Glu76Asp	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.228G>C	p.Glu76Asp	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.228G>C	p.Glu76Asp	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461524 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727088

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.228G>C; p.Glu76Asp variant (rs397507514) is reported in the literature in individuals with Noonan syndrome (Chinton 2019, Li 2019, Tartaglia 2001), and is reported in ClinVar (Variation ID: 40503). Functional analyses show that this variant causes destabilization of the interdomain interface and in vitro phosphatase activity is altered (Bocchinfuso 2007). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.703). Additionally, other variants at this codon (Ala, Gly, Lys and Val) have been reported in individuals with Noonan syndrome or juvenile myelomonocytic leukemia and are considered disease-causing (Tartaglia 2001, Tartaglia 2003). Based on available information, this variant is considered to be pathogenic. References: Bocchinfuso G et al. Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2. Proteins. 2007 Mar 1;66(4):963-74. PMID: 17177198. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. English, Spanish. PMID: 31560489. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759. Tartaglia M et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID: 12717436. -

Jan 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the presence of the E76D variant causes increased basal catalytic activity in comparison to wild-type protein (Bocchinfuso et al., 2007); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15987685, 20308328, 24803665, 26607044, 11704759, 28084675, 30417923, 31219622, 31560489, 33318624, 34643321, 17177198, 24077912, 11992261, 9491886, 16053901, 29493581) -

RASopathy Pathogenic:2

Dec 26, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PTPN11 c.228G>C (p.Glu76Asp) variant involves the alteration of a conserved nucleotide located at the SH2 domain of the protein (InterPro, Keilhack _2005, Edouard_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 215446 control chromosomes (gnomAD). This variant has been reported in many individuals with NS (Tartaglia_2001, Aoki_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies showed variant with mild (2.5-3.1 fold) basal activation compared with WT (Keilhack _2005 and Niihori_2005). A variant involving the same nucleotide, c.228G>T, leading to the same codon change E76D, has been reported in affected individuals and was classified as pathogenic by our lab, suggesting the functional importance of this codon. Taken together, this variant is classified as pathogenic. -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16358218, 16830086, 18678287, 19077116, 22190897). ClinVar contains an entry for this variant (Variation ID: 40503). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 11704759, 15834506, 17177198). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome 1 Pathogenic:1

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Pathogenic:1

Oct 05, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu76Asp variant has been reported in at least 7 individuals with clinical f eatures of Noonan syndrome (Tartaglia 2006, Tartaglia 2001). Therefore, this var iant is highly likely to be pathogenic. The presence of a heterozygous pathogeni c variant in PTPN11 is consistent with a diagnosis of Noonan syndrome but this i nformation should be reconciled with the complete clinical history of this indiv idual. -

Cardiovascular phenotype Pathogenic:1

Nov 11, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E76D pathogenic mutation (also known as c.228G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 228. The glutamic acid at codon 76 is replaced by aspartic acid, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Ferrero GB et al. Eur J Med Genet Jul;51:566-72). An alternate nucleotide change, c.228G>T, resulting in the same amino acid substitution p.E76D, has also been detected in Noonan syndrome cohorts (Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Functional studies have shown that p.E76D leads to increased phosphatase activity (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Keilhack H et al. J. Biol. Chem., 2005 Sep;280:30984-93). 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	1.0
CardioboostCm	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;D
Eigen	Benign	-0.014
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.1	L;L;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	D;D;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.022	D;D;.;.
Sift4G	Benign	0.13	T;T;.;T
Polyphen		0.38	B;P;.;.
Vest4		0.91
MutPred		0.89		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.99
MPC		1.7
ClinPred		0.95	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
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: rs397507514; hg19: chr12-112888212;