ClinVar Miner

Submissions for variant NM_002755.3(MAP2K1):c.199G>A (p.Asp67Asn) (rs727504317)

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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 RCV000208771 SCV000616531 pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation The c.199G>A (p.Asp67Asn) variant in MAP2K1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17704260). In vitro functional studies provide some evidence that the p.Asp67Asn variant may impact protein function (PS3; PMID 25049390). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Asp67Asn variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PP2, PP3.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844673 SCV000204064 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2014-10-31 criteria provided, single submitter clinical testing The p.Asp67Asn variant in MAP2K1 has been identified in 9 individuals with clini cal features of Noonan syndrome and/or Cardio-facio-cutaneous syndrome including 2 de novo occurences (Nava 2007, LMM unpublished data). This variant was absent from large population studies. In vitro functional studies provide some evidenc e that the p.Asp67Asn variant may impact protein function (Estep 2007). However, these types of assays may not accurately represent biological function. This va riant has also been reported in tumor samples from 2 individuals with colon canc er (Murugan 2009, Choi 2012). In summary, this variant meets our criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner (http:/ /www.partners.org/personalizedmedicince/LMM) based upon de novo occurrences, abs ence from controls, and functional evidence.
GeneDx RCV000212506 SCV000207939 pathogenic not provided 2017-09-25 criteria provided, single submitter clinical testing The D67N variant has been reported previously in association with cardiofaciocutaneous syndrome and Noonan syndrome, including apparently de novo occurrences (Nava et al., 2007). It has also been observed to occur de novo in individuals tested at GeneDx. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D67N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies revealed that D67N variant expression in human embryonic kidney cells caused constitutive ERK activation; under the same conditions, wild type cells had little effect, suggesting the D67N variant is disease-causing (Chen et al., 2014).
Invitae RCV000158004 SCV000544722 pathogenic Rasopathy 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 67 of the MAP2K1 protein (p.Asp67Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Noonan syndrome or cardio-facio-cutaneous syndrome (PMID: 17704260, 25049390). It was shown to be de novo in at least two of these individuals. ClinVar contains an entry for this variant (Variation ID: 40781). Experimental studies have shown that this missense change results in constitutive ERK activation in cell culture (PMID: 25049390). For these reasons, this variant has been classified as Pathogenic.
Liping Wei Laboratory,Peking University RCV000754677 SCV000804769 pathogenic Autism spectrum disorder 2018-08-01 criteria provided, single submitter research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000192193 SCV000898812 pathogenic Cardiofaciocutaneous syndrome 3 2017-11-16 criteria provided, single submitter clinical testing MAP2K1 NM_02755.3 p.Asp67Asn (c.199G>A): This variant has been reported in the literature in at least 5 individuals with Noonan syndrome or Cardio-Facio-Cutaneous syndrome (Nava 2007 PMID:17704260; Chen 2014 PMID:25049390; Carcavilla 2015 PMID:25194980) including 2 de novo cases (Nava 2007 PMID:17704260) and is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 40781). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, in vitro (Chen 2014 PMID:25049390; Estep 2014 PMID: 18060073) and in vivo (Jindal 2016 PMID:2804985) functional studies suggest a deleterious effect of this variant. In summary, this variant is classified as pathogenic based on presence of affected individuals (including de novo occurences), absence from controls, and functional studies.
GeneReviews RCV000192193 SCV000223060 pathogenic Cardiofaciocutaneous syndrome 3 2015-05-14 no assertion criteria provided literature only
GeneReviews RCV000208771 SCV000264639 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439184 SCV000504537 pathogenic Non-small cell lung cancer 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423708 SCV000504538 likely pathogenic Cutaneous melanoma 2015-07-14 no assertion criteria provided literature only

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