Description
The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia 2006 PMID: 16358218, Power 2006 PMID: 16830086, Digilio 2011 PMID: 22190897, Zhu 2018 PMID: 30029678, Leach 2019 PMID: 29907801, LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 40502). It was absent from large population studies. Notably, a different nucleotide substitution at the same position (c.228G>C) resulting in the same amino acid change has been reported in >10 individuals with clinical features of Noonan syndrome (Tartaglia 2001 PMID: 11704759, Tartaglia 2006 PMID: 16358218, Edouard 2010 PMID: 20308328, LMM data). In addition, there are 4 other pathogenic amino acid substitutions at this position (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly); all these variants were also absent in large population studies. In vitro functional studies support an impact on protein function (Keilhack 2005 PMID: 15987685, Bocchinfuso 2007 PMID: 17177198, Edouard 2010 PMID: 20308328). Additionally, this variant lies in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (Gelb 2018 PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Strong, PS3_Supporting.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |