Submissions for variant NM_030662.4(MAP2K2):c.814G>A (p.Ala272Thr)

gnomAD frequency: 0.00001  dbSNP: rs757240576

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000680366	SCV000573852	likely benign	not provided	2020-12-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000482431	SCV000709727	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 19:4099304 C / T: Total 4/230480; not well conserved Platypus, Naked_mole rat, and Zebra_mbuna(fish) have threonine; Not in Pubmed, Google search or HGMD; VUS by GeneDx in ClinVar; benign by polyphen
Ambry Genetics	RCV002420244	SCV002681758	uncertain significance	Cardiovascular phenotype	2022-10-09	criteria provided, single submitter	clinical testing	The p.A272T variant (also known as c.814G>A), located in coding exon 7 of the MAP2K2 gene, results from a G to A substitution at nucleotide position 814. The alanine at codon 272 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526970	SCV003523256	uncertain significance	RASopathy	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 272 of the MAP2K2 protein (p.Ala272Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 424075). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAP2K2 protein 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.
Revvity Omics, Revvity	RCV003129871	SCV003808262	uncertain significance	Cardiofaciocutaneous syndrome 4	2022-09-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003129871	SCV003842967	uncertain significance	Cardiofaciocutaneous syndrome 4	2022-12-19	criteria provided, single submitter	clinical testing	The MAP2K2 c.814G>A (p.Ala272Thr) missense change has a maximum subpopulation frequency of 0.0071% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign 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.?
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003129871	SCV004565227	uncertain significance	Cardiofaciocutaneous syndrome 4	2023-06-27	criteria provided, single submitter	clinical testing	The MAP2K2 c.814G>A; p.Ala272Thr variant (rs757240576), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 424075). This variant is observed in the general population with an overall allele frequency of 0.002% (4/233976 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.058). Due to limited information, the clinical significance of this variant is uncertain at this time.