ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.461G>C (p.Gly154Ala)

gnomAD frequency: 0.00002  dbSNP: rs376027245
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521157 SCV000620336 uncertain significance not provided 2023-03-31 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV001245865 SCV001419186 uncertain significance RASopathy 2024-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 154 of the PTPN11 protein (p.Gly154Ala). This variant is present in population databases (rs376027245, gnomAD 0.008%). 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: 451613). Invitae Evidence 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 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.
Ambry Genetics RCV003302760 SCV004000118 uncertain significance Cardiovascular phenotype 2023-05-03 criteria provided, single submitter clinical testing The p.G154A variant (also known as c.461G>C), located in coding exon 4 of the PTPN11 gene, results from a G to C substitution at nucleotide position 461. The glycine at codon 154 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003444566 SCV004171427 uncertain significance Noonan syndrome 1 2023-11-28 criteria provided, single submitter clinical testing The PTPN11 c.461G>C (p.Gly154Ala) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant occurs in a gene where missense variants are a common mechanism of disease. The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in individuals with RASopathy conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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