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

gnomAD frequency: 0.00004  dbSNP: rs151133017

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767154	SCV000207966	uncertain significance	not provided	2023-12-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29493581)
Laboratory for Molecular Medicine, Mass General Brigham 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 Molecular Pathology, St. Jude Children's Research Hospital	RCV000761056	SCV000890971	uncertain significance	Noonan syndrome	2020-09-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062526	SCV001227333	uncertain significance	RASopathy	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the MAP2K2 protein (p.Arg313Gln). This variant is present in population databases (rs151133017, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 40839). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt MAP2K2 function with a negative predictive value of 95%. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813318	SCV002060809	uncertain significance	Noonan syndrome and Noonan-related syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371815	SCV002684960	uncertain significance	Cardiovascular phenotype	2024-02-26	criteria provided, single submitter	clinical testing	The c.938G>A (p.R313Q) alteration is located in exon 8 (coding exon 8) of the MAP2K2 gene. This alteration results from a G to A substitution at nucleotide position 938, causing the arginine (R) at amino acid position 313 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002482944	SCV002780982	uncertain significance	Cardiofaciocutaneous syndrome 4	2021-07-09	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002482944	SCV003928066	uncertain significance	Cardiofaciocutaneous syndrome 4	2023-03-27	criteria provided, single submitter	clinical testing	The MAP2K2 c.938G>A (p.Arg313Gln) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with cardiofaciocutanous syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000767154	SCV004224523	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing
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.