12-112450385-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PS2PM2PP3PP2PS4
This summary comes from the ClinGen Evidence Repository: The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID:12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hématologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hématologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID:26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID:29493581). PTPN11 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 analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261565/MONDO:0021060/004
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.205G>C | p.Glu69Gln | missense_variant | Exon 3 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.205G>C | p.Glu69Gln | missense_variant | Exon 3 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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 a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 15928039, 24803665, 12634870, 23624134, 23321623, 26817465, 15001945, 31560489, 32164556, 31130284, 34643321, 36566191, 35979676, 11992261, 9491886, 16053901, 29493581) -
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RASopathy Pathogenic:4
Variant classified using ACMG guidelines -
The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID: 12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hematologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hematologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID: 26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID: 29493581). PTPN11 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 analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3. -
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 69 of the PTPN11 protein (p.Glu69Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12634870, 15001945, 20186801, 23321623, 23624134, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40498). 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%. This variant disrupts the p.Glu69 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been observed in individuals with PTPN11-related conditions (PMID: 19077116, 20186801, 20578946), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: PTPN11 c.205G>C (p.Glu69Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251636 control chromosomes (gnomAD and publication data). c.205G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome including one individual determined as de novo (Musante_2003, Zenker_2004, Pierpont_2010, Croonen_2013, Atik_2016, Chinton_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014), including one expert panel (ClinGen RASopathy Variant Curation Expert Panel), cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Noonan syndrome 1 Pathogenic:1
PM2_Supporting+PP2+PP3+PS4+PM6_Strong+PM1 -
Noonan syndrome Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Cardiovascular phenotype Pathogenic:1
The p.E69Q pathogenic mutation (also known as c.205G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 205. The glutamic acid at codon 69 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with Noonan syndrome, including at least one case reported to be de novo (Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Bertelloni S et al. Hormones (Athens), 2013 Jan-Mar;12:86-92; Croonen EA et al. Eur. J. Hum. Genet., 2013 Sep;21:936-42; izmárová M et al. Ann. Hum. Genet., 2016 Jan;80:50-62; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21). 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