ClinVar Miner

Submissions for variant NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val) (rs144080051)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000519375 SCV000616535 benign Rasopathy 2017-05-09 reviewed by expert panel curation The filtering allele frequency of the c.848C>T (p.Ala283Val) variant in the MAP2K1 gene is 0.052% for African chromosomes by the Exome Aggregation Consortium (10/10366 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data; GTR ID: 21766, 26957; ClinVar SCV000207935.12; SCV000061262.5). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037602 SCV000061262 likely benign not specified 2014-01-28 criteria provided, single submitter clinical testing Ala283Val in exon 7 of MAP2K1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, Egyptian jerboa and dog have a valine (Val) at this position despite high ne arby amino acid conservation. In addition, computational analyses (PolyPhen2, SI FT, AlignGVGD) do not suggest a high likelihood of impact to the protein. This v ariant has been identified in 0.1% (5/4402) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14 4080051).
GeneDx RCV000037602 SCV000207935 likely benign not specified 2015-07-28 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 RCV000037602 SCV001338958 likely benign not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: MAP2K1 c.848C>T (p.Ala283Val) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251410 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is significantly above 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 African or African-American origin. To our knowledge, no occurrence of c.848C>T 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. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000519375 SCV001412748 uncertain significance Rasopathy 2020-07-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 283 of the MAP2K1 protein (p.Ala283Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs144080051, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MAP2K1-related disease. ClinVar contains an entry for this variant (Variation ID: 40756). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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