Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV004017410 | SCV000712324 | uncertain significance | not provided | 2021-08-06 | criteria provided, single submitter | clinical testing | The p.Glu532Lys variant in PTPN11 was identified in 1 individual with Noonan syndrome and 1 individual with CFC, but was also identified in two unaffected relatives from two different families (Brasil 2010 PMID: 20578946, LMM data). It has also been identified in 0.0086% (3/34592) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 135111). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain though the available data suggests it is likely benign. ACMG/AMP Criteria applied: BS4. |
Genome Diagnostics Laboratory, |
RCV001813380 | SCV002060836 | uncertain significance | Noonan syndrome and Noonan-related syndrome | 2021-05-28 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001854671 | SCV002176997 | uncertain significance | RASopathy | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 532 of the PTPN11 protein (p.Glu532Lys). This variant is present in population databases (rs587778634, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 135111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Fulgent Genetics, |
RCV002483228 | SCV002781341 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2022-05-26 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003298143 | SCV004000112 | uncertain significance | Cardiovascular phenotype | 2023-06-13 | criteria provided, single submitter | clinical testing | The p.E532K variant (also known as c.1594G>A), located in coding exon 13 of the PTPN11 gene, results from a G to A substitution at nucleotide position 1594. The glutamic acid at codon 532 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a Noonan-like syndrome cohort (Brasil AS et al. Genet Test Mol Biomarkers, 2010 Jun;14:425-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Pittsburgh Clinical Genomics Laboratory, |
RCV004783747 | SCV005397396 | uncertain significance | Noonan syndrome 1 | 2023-06-06 | criteria provided, single submitter | clinical testing | This sequence variant is a single nucleotide substitution (G>A) at position 1594 of the coding sequence of the PTPN11 gene that results in a glutamic acid to lysine amino acid change at residue 532 of the protein tyrosine phosphatase non-receptor type 11 protein. This is a previously reported variant (ClinVar 135111) that has been observed in an individual affected by Noon-like syndrome with clinical features of cardiofaciocutaneous syndrome (PMID: 20578946) and a member of a cohort affected by neurodevelopmental disorders (PMID: 28191889). However, this variant has also been observed in uffected individuals (PMID: 20578946, 24728327). This variant is present in 4 of 251406 alleles (0.0016%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this glutamic acid to lysine amino acid change would be damaging, and the glutamic acid residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3 |
ITMI | RCV000121910 | SCV000086114 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |