ClinVar Miner

Submissions for variant NM_002755.4(MAP2K1):c.439-19C>A

gnomAD frequency: 0.00010  dbSNP: rs766207567
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000437721 SCV000523913 likely benign not provided 2017-06-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199938 SCV001370726 benign not specified 2020-05-18 criteria provided, single submitter clinical testing Variant summary: MAP2K1 c.439-19C>A 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. Several computational tools predict a significant impact on normal splicing: Four predict that the variant creates or strengthens a cryptic intronic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 251366 control chromosomes, predominantly at a frequency of 0.00016 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 64-fold 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.439-19C>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV002065058 SCV002486183 likely benign RASopathy 2023-12-01 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000437721 SCV005210952 likely benign not provided criteria provided, single submitter not provided

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