Submissions for variant NM_002834.5(PTPN11):c.643-6dup

gnomAD frequency: 0.00030  dbSNP: rs758889732

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000520386	SCV000616447	likely benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.643-6dupG variant in the PTPN11 gene is 0.0461% (9/10166) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
Invitae	RCV000520386	SCV001016267	likely benign	RASopathy	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193112	SCV001361729	likely benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.643-6dupG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250408 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome And Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.643-6dupG in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters, including one expert panel (ClinGen), (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001712480	SCV001943845	benign	not provided	2018-11-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001193112	SCV002068110	likely benign	not specified	2020-04-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002506264	SCV002801230	likely benign	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-04-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541625	SCV004775549	likely benign	PTPN11-related disorder	2023-12-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).