ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.244A>G (p.Met82Val) (rs397507515)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522529 SCV000616408 uncertain significance Rasopathy 2017-04-03 reviewed by expert panel curation The c.244A>G p.Met82Val variant in PTPN11 has been identified in patients with clinical features of a RASopathy (PS4 not met; GeneDx, EGL genetics internal data; GTR ID's: 26957, 500060; SCV000057386.11; SCV000228999.4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID's: 26957; SCV000057386.11). 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). In summary, the clinical significance of the p.Met82Val variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, PP2.
GeneDx RCV000724722 SCV000057386 uncertain significance not provided 2014-03-10 criteria provided, single submitter clinical testing The M82V missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Server reports M82V was not observed in approximately 6,200 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations, and M82V is also not present in the 1000 Genomes Database. M82V is located at a conserved position within the N-SH2 domain of the SHP2 protein encoded by PTPN11. This domain is the first of two sites involved in switching the protein between its inactive and active conformations. Missense mutations at nearby positions (Q79P, Q79R, D106A) have been reported previously in association with Noonan syndrome. However, the M82V amino acid change is conservative in that both Methionine and Valine are uncharged, non-polar amino acids, and multiple in-silico analysis models predict that M82V is a benign sequence change. Therefore, based on the currently available information, it is unclear whether M82V is a disease-causing mutation or a rare benign variant. The variant is found in NOONAN panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724722 SCV000228999 uncertain significance not provided 2015-04-16 criteria provided, single submitter clinical testing

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