Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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). |
Gene |
RCV001719721 | SCV000207935 | benign | not provided | 2020-03-18 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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. |
Labcorp Genetics |
RCV000519375 | SCV001412748 | likely benign | RASopathy | 2024-01-22 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV001719721 | SCV002050161 | likely benign | not provided | 2021-04-09 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV004018723 | SCV003692334 | likely benign | Cardiovascular phenotype | 2021-07-19 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. |
Prevention |
RCV004532502 | SCV004714833 | benign | MAP2K1-related disorder | 2021-03-31 | no assertion criteria provided | 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). |