ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.333-3T>C (rs146749153)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000719608 SCV000850477 uncertain significance History of neurodevelopmental disorder 2017-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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.
Integrated Genetics/Laboratory Corporation of America 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 2018-12-18 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs146749153, ExAC 0.06%). This variant has not been reported in the literature in individuals with PTPN11-related disease. ClinVar contains an entry for this variant (Variation ID: 40511). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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