ClinVar Miner

Submissions for variant NM_030662.4(MAP2K2):c.938G>A (p.Arg313Gln) (rs151133017)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767154 SCV000207966 uncertain significance not provided 2012-06-21 criteria provided, single submitter clinical testing This variant is denoted c.938 G>A at the cDNA level or p.Arg313Gln (R313Q) at the protein level. The R313Q missense substitution has not been published as a mutation nor as a benign polymorphism, to our knowledge. The R313Q amino acid substitution is a non-conservative change, with a positively charged residue (Arg) being replaced by a neutral residue (Gln). The R313 position is conserved in the MAP2K2 protein but not in related proteins. Although the majority of missense variants in MAP2K2 are pathogenic, no disease-causing mutation has been reported after codon 273. Therefore, the R313Q missense change could either be a disease-causing mutation or a benign polymorphism. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000158031 SCV000709724 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: GnomAd 19:4097323 C / T: European 9/126472; well conserved; Not in Pubmed, Google search or HGMD; VUS by GeneDx in ClinVar; probably damaging by polyphen
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761056 SCV000890971 uncertain significance Noonan syndrome 2020-09-22 criteria provided, single submitter clinical testing
Invitae RCV001062526 SCV001227333 uncertain significance Rasopathy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 313 of the MAP2K2 protein (p.Arg313Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs151133017, ExAC 0.01%). This variant has not been reported in the literature in individuals with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 40839). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000767154 SCV001553629 uncertain significance not provided no assertion criteria provided clinical testing The MAP2K2 p.R313Q variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs151133017) and in ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine, GeneDx, and Clinical Genomics Lab at St. Jude Children's Research Hospital with associated condition of B Lymphoblastic Leukemia/Lymphoma with t(v;11q23.3); KMT2A Rearranged). The variant was identified in control databases in 14 of 282142 chromosomes (0 homozygous) at a frequency of 0.00005 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 4 of 30608 chromosomes (freq: 0.000131), African in 2 of 24896 chromosomes (freq: 0.00008) and European (non-Finnish) in 8 of 128808 chromosomes (freq: 0.000062), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The p.Arg313 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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