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

gnomAD frequency: 0.00029  dbSNP: rs144080051

Total submissions: 8

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, Mass General Brigham 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	RCV001719721	SCV000207935	benign	not provided	2020-03-18	criteria provided, single submitter	clinical testing
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	likely benign	RASopathy	2024-01-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001719721	SCV002050161	likely benign	not provided	2021-04-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513330	SCV003692334	likely benign	Inborn genetic diseases	2021-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003894845	SCV004714833	benign	MAP2K1-related condition	2021-03-31	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).