Submissions for variant NM_002834.5(PTPN11):c.333-3T>C

gnomAD frequency: 0.00026  dbSNP: rs146749153

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033488	SCV000616444	likely benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.333-3T>C variant in the PTPN11 gene is 0.0276% (6/9456) 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)
GeneDx	RCV000033488	SCV000057393	poly	RASopathy		criteria provided, single submitter	clinical testing	Converted during submission to Benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213919	SCV000272339	uncertain significance	not specified	2016-11-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.333-3T>C vari ant in PTPN11 has identified by our laboratory in 1 mixed ethnicity individual w ith DCM and was also identified in their unaffected parent. It has also been ide ntified in 6/9456 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146749153). This variant is located in the 5' splice region. The Cytosine (C) nucleotide at position 331-3 is consisten t with the consensus splice sequence and computational tools do not suggest an i mpact to splicing. However, this information is not predictive enough to rule ou t pathogenicity. In summary, while the clinical significance of the c.333-3T>C v ariant is uncertain, these data suggest that it is more likely to be benign.
Ambry Genetics	RCV002316204	SCV000850477	likely benign	Cardiovascular phenotype	2019-10-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213919	SCV000920093	benign	not specified	2018-02-26	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.333-3T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. Two predict this variant creates a cryptic splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 276356 control chromosomes. The observed variant frequency within African control individuals in the gnomAD database is approximately 11.36 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 origin. To our knowledge, no occurrence of c.333-3T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000033488	SCV000933666	uncertain significance	RASopathy	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the PTPN11 gene. It does not directly change the encoded amino acid sequence of the PTPN11 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs146749153, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 40511). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
CeGaT Center for Human Genetics Tuebingen	RCV003390717	SCV004131961	benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	PTPN11: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003894844	SCV004711068	likely benign	PTPN11-related condition	2021-10-06	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).