12-112489106-G-C
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2PP3PM2PM5_StrongPM6_Strong
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
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
Publications
- LEOPARD syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
- Noonan syndrome with multiple lentiginesInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- metachondromatosisInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
- cardiofaciocutaneous syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | MANE Select | c.1530G>C | p.Gln510His | missense | Exon 13 of 16 | NP_002825.3 | ||
| PTPN11 | NM_001330437.2 | c.1542G>C | p.Gln514His | missense | Exon 13 of 16 | NP_001317366.1 | |||
| PTPN11 | NM_001374625.1 | c.1527G>C | p.Gln509His | missense | Exon 13 of 16 | NP_001361554.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | TSL:1 MANE Select | c.1530G>C | p.Gln510His | missense | Exon 13 of 16 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | TSL:5 | c.1542G>C | p.Gln514His | missense | Exon 13 of 15 | ENSP00000489597.1 | ||
| PTPN11 | ENST00000635652.1 | TSL:3 | c.543G>C | p.Gln181His | missense | Exon 5 of 5 | ENSP00000489541.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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
RASopathy Pathogenic:2
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.
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.
LEOPARD syndrome 1 Pathogenic:1
Metachondromatosis Pathogenic:1
PTPN11-related disorder Pathogenic:1
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.
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Cardiovascular phenotype Pathogenic:1
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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at