chr12-112489106-G-C

Position:

• chr12-112489106-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5_Strong PM2 PM6_Strong PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3). At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM5_Strong, PM2, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220143/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• 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 12 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1530G>C	p.Gln510His	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1542G>C	p.Gln514His	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1527G>C	p.Gln509His	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1539G>C	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>C	p.Gln510His	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1542G>C	p.Gln514His	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.543G>C	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:14

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2019	- -
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	GeneDx	Jan 19, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 24234437, 25232094, 31263281, 31560489, 33318624, 31277675, 21910226) -

Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Apr 20, 2023	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2018	Variant summary: PTPN11 c.1530G>C (p.Gln510His) results in a non-conservative amino acid change affecting a critical amino acid located in the PTP type protein phosphatase 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 30972 control chromosomes. c.1530G>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One was the "ClinGen RASopathy Expert Panel" which classified this variant as Pathogenic, while the other classified it as "Likely Pathogenic" without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3). At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM5_Strong, PM2, PP3, PP2. -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2022

- -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2022

- -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

The PTPN11 c.1530G>C variant is predicted to result in the amino acid substitution p.Gln510His. This variant has been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (Table 1, Wakabayashi et al. 2011. PubMed ID: 21910226; Table 3, Chinton et al. 2019. PubMed ID: 31560489; Table S2, Kauffman et al. 2020. PubMed ID: 33318624). Moreover, this variant has been reported as having arisen de novo in an individual with Noonan syndrome with multiple lentigines (Table 1, Li et al. 2019. PubMed ID: 31263281). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40567/). Alternate nucleotide changes affecting the same amino acid (p.Gln510Glu, p.Gln510Pro, and p.Gln510Arg) have been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (Digilio et al. 2006. PubMed ID: 16733669; Keren et al. 2004. PubMed ID: 15520399; Bertola et al. 2005. PubMed ID: 15948193). In summary, the p.Gln510His variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The p.Q510H pathogenic mutation (also known as c.1530G>C), located in coding exon 13 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1530. The glutamine at codon 510 is replaced by histidine, an amino acid with highly similar properties. This variant as been reported in multiple individuals with PTPN11-related RASopathy (Wakabayashi Y et al. Am. J. Med. Genet. A, 2011 Oct;155A:2529-33; Chinton J et al. Arch Argent Pediatr, 2019 Oct;117:330-337; Kauffman H et al. Pediatr Res, 2021 Aug;90:444-451). It has also been determined to be the result of a de novo mutation in a fetus with features including hydrops fetalis, pleural effusion, cardiomyopathy, and hepatomegaly (Stuurman KE et al. J Med Genet, 2019 Oct;56:654-661). Another variant at the same codon, c.1530G>T (p.Q510H), has been described previously in fetuses with cystic hygroma (Gezdirici A et al. J Matern Fetal Neonatal Med, 2017 Apr;30:938-941). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 03, 2021

- -

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	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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

LitVar

Other links and lift over

dbSNP: rs397507550; hg19: chr12-112926910; COSMIC: COSV61005626; COSMIC: COSV61005626;