ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.173A>G (p.Asn58Ser) (rs751437780)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413828 SCV000490755 uncertain significance not provided 2018-04-12 criteria provided, single submitter clinical testing The N58S variant in the PTPN11 gene has been observed previously as a somatic variant in a lung cancer cell line (Bentires-Alj et al., 2004) and as a germline variant in an individual with childhood acute lymphoblastic leukemia (Case et al., 2008). The N58S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. It occurs at a position that is within the N-SH2 domain of the gene, a hot spot for Noonan syndrome variants. Additionally, this is the first of two sites involved in switching the protein between its inactive and active conformations. Other missense variants in the same residue (N58H, N58D, N58K) have been reported in HGMD in association with Noonan syndrome (Stenson et al., 2014) and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the N58S variant is observed in 10/126236 (0.008%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts, indicating it may be a rare benign variant in this population. (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000691488 SCV000819269 uncertain significance Rasopathy 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 58 of the PTPN11 protein (p.Asn58Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs751437780, ExAC 0.003%). This variant has not been reported in the literature in individuals with PTPN11-related disease. ClinVar contains an entry for this variant (Variation ID: 372483). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Asn58 amino acid residue in PTPN11 have been observed in affected individuals (PMID: 15956085, 16804314, 19125092, 25914815, 16263833). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Integrated Genetics/Laboratory Corporation of America RCV000780655 SCV000918108 uncertain significance not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.173A>G (p.Asn58Ser) results in a conservative amino acid change located in the first 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 observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.26 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.173A>G in individuals affected with Noonan Syndrome and Related Conditions has been reported. However, c.173A>G (p.Asn58Ser) has been observed previously as a somatic mutation in a lung cancer cell line (Bentires-Alj 2004) and was reported in association with childhood acute lymphoblastic leukemia in an individual as a somatic and germline variant (Case 2008). Other missense variants affecting the same amino acid position have been reported in Noonan syndrome (N58K, N58D, N58K; Kratz 2005, Tartaglia 2006) and childhood acute leukemia (N58Y, somatic, Tartaglia 2004); these reports might indicate the importance of this residue for protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. The c.173A>G has been identified in an internal sample undergoing genetic testing due to abnormal US findings and was confirmed to be is maternally inherited. However, mother was not evaluated by clinical geneticist and, therefore association of N58S with NS remains to be established (internal data). Based on the evidence outlined above, the variant was classified as uncertain significance.

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