ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1746C>T (p.Asn582=) (rs397516800)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037628 SCV000061290 benign not specified 2015-04-07 criteria provided, single submitter clinical testing p.Asn582Asn in exon 15 of PTPN11: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 4/15702 South As ian chromosomes and 8/63828 European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516800 ). Furthermore, it has been identified by our laboratory in an unaffected mother and 2 individuals with features of Noonan syndrome, one of which also carried another variant in PTPN11 sufficient to explain their disease.
PreventionGenetics,PreventionGenetics RCV000037628 SCV000309205 likely benign not specified criteria provided, single submitter clinical testing
Invitae RCV000546916 SCV000659039 likely benign Rasopathy 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619648 SCV000740265 likely benign Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037628 SCV001362748 benign not specified 2019-06-10 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1746C>T results in a synonymous change. 5/5 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 0.0001 in 250916 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-folds higher than 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 Non-Finnish European origin. To our knowledge, no occurrence of c.1746C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.

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