ClinVar Miner

Submissions for variant NM_002755.4(MAP2K1):c.1068+12_1068+15del (rs397516788)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000157994 SCV000616558 benign Rasopathy 2017-05-09 reviewed by expert panel curation The filtering allele frequency of the c.1068+12_1068+15delTATT variant in the MAP2K1 gene is 0.285% (214/66740) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037588 SCV000061246 likely benign not specified 2015-08-28 criteria provided, single submitter clinical testing c.1068+12_1068+15delTATT in intron 10 of MAP2K1: 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 0 .3% (214/66740) of European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org).
GeneDx RCV000157994 SCV000207929 benign Rasopathy 2012-08-21 criteria provided, single submitter clinical testing The variant is found in NOONAN panel(s).
PreventionGenetics,PreventionGenetics RCV000037588 SCV000309170 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000296799 SCV000393417 uncertain significance Noonan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000349253 SCV000393418 uncertain significance Cardio-facio-cutaneous syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000157994 SCV000556849 benign Rasopathy 2020-11-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037588 SCV001360551 benign not specified 2019-10-08 criteria provided, single submitter clinical testing Variant summary: MAP2K1 c.1068+12_1068+15delTATT 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 251462 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1440 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), 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.1068+12_1068+15delTATT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions including an expert panel, ClinGen, (evaluation after 2014) cite the variant three times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000296799 SCV001439178 benign Noonan syndrome 2020-09-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289721 SCV001477697 likely benign none provided 2020-02-03 criteria provided, single submitter clinical testing

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