chr12-112489106-G-T

Position:

• chr12-112489106-G-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1530G>T​(p.Gln510His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q510E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.71

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]

PTPN11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 23 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 16) in uniprot entity PTN11_HUMAN there are 6 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 chr12-112489104-C-G is described in Lovd as [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, 0.985
• PP5: Variant 12-112489106-G-T is Pathogenic according to our data. Variant chr12-112489106-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 811634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1530G>T	p.Gln510His	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1542G>T	p.Gln514His	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1527G>T	p.Gln509His	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1539G>T	p.Gln513His	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1530G>T	p.Gln510His	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1542G>T	p.Gln514His	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.543G>T	p.Gln181His	missense_variant	5/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 20, 2019

The PTPN11 c.1530G>T; p.Gln510His variant (rs397507550) is reported in the literature in two unrelated fetuses with prenatal symptoms of Noonan syndrome, and it was not observed in the parents of either affected fetus, indicating a de novo origin (Gezdirici 2017). Additionally, a variant giving rise to the same amino acid change (c.1530G>C; p.Gln510His) was observed in an individual affected with LEOPARD syndrome (Wakabayashi 2011). The c.1530G>T; p.Gln510His variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamine at codon 510 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Arg, Glu, and Pro) have been reported in individuals with Noonan syndrome or LEOPARD syndrome and are considered pathogenic (Aoki 2008, Carcavilla 2013, Ganigara 2011, Wakabayashi 2011). Based on available information, the p.Gln510His variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. Ganigara M et al. LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation. Ann Pediatr Cardiol. 2011 Jan;4(1):74-6. Gezdirici A et al. How necessary is to analyze PTPN11 gene in fetuses with first trimester cystic hygroma and normal karyotype? J Matern Fetal Neonatal Med. 2017 Apr;30(8):938-941. Wakabayashi Y et al. Implantable cardioverter defibrillator for progressive hypertrophic cardiomyopathy in a patient with LEOPARD syndrome and a novel PTPN11 mutation Gln510His. Am J Med Genet A. 2011 Oct;155A(10):2529-33. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2023

The PTPN11 c.1530G>T variant is predicted to result in the amino acid substitution p.Gln510His. This variant has been reported in prenatal cases with cystic hygroma (Gezdirici et al. 2017. PubMed ID: 27193571; Supplemental Table S2, Leach et al. 2018. PubMed ID: 29907801) and hydrops fetalis (Supplemental Table 1, Gabriel et al. 2021. PubMed ID: 34958143). Of note, another variant impacting the p.Gln510 amino acid was also reported in prenatal cases with cystic hygroma [c.1530G>T (p.Gln510His), Supplemental Table S2, Leach et al. 2018. PubMed ID: 29907801]. In addition, another variant impacting the p.Gln510 amino acid was also reported in an individual tested for Noonan syndrome and related conditions [c.1528C>G (p.Gln510Glu), Supplemental Table S3, Leach et al. 2018. PubMed ID: 29907801]. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2020

- -

Noonan syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.4	D;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.93		Loss of MoRF binding (P = 0.1112);.;.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.90
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112926910; COSMIC: COSV61006865; COSMIC: COSV61006865;