Submissions for variant NM_002834.5(PTPN11):c.211T>G (p.Phe71Val)

dbSNP: rs397507512

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159044	SCV000208986	pathogenic	not provided	2014-07-17	criteria provided, single submitter	clinical testing	The F71V mutation has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The F71V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F71V mutation is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in this residue and in nearby residues (Y63C, E69Q, E69V, F71I, F71L, A72G, A72P, A72S, T73I, E76A, E76D, E76G, E76V) have been reported in association with PTPN11-related disorders, supporting the functional importance of this region of the protein. Therefore, F71V is considered to be a disease-causing mutation. The variant is found in NOONAN panel(s).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004593995	SCV005086426	pathogenic	Noonan syndrome 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187; ClinGen expert panel). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants within the SH2 domain (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants, p.(Phe71Ile) and p.(Phe71Leu), have been reported many times as pathogenic, and observed in individuals with Noonan syndrome, or with short stature and growth hormone deficiency (PMID: 15834506, PMID: 36714562). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported once as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign