Submissions for variant NM_002755.4(MAP2K1):c.371C>T (p.Pro124Leu)

dbSNP: rs397516792

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037595	SCV000061253	likely pathogenic	Cardio-facio-cutaneous syndrome	2010-09-02	criteria provided, single submitter	clinical testing	The Pro124Leu variant has been identified in one individual with clinical featur es of Cardio-facio-cutaneous syndrome (Narumi 2007). In addition, a different am ino acid change at this location (Pro124Gln) was identified as a de novo variant in an indidual with clinical features of Cardio-facio-cutaneous syndrome and Co stello syndrome (Gripp 2007). Therefore, this variant is likely to be pathogenic .
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037595	SCV000698035	pathogenic	Cardio-facio-cutaneous syndrome	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The MAP2K1 c.371C>T (p.Pro124Leu) variant causes a missense change involving the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest is absent from large, broad control datasets of ExAC and gnomAD (~121408 and 246224 control chromosomes tested). This variant was reported as a germline variant in at least one patient with presented with Cardio-Facio-Cutaneous syndrome (CFC) (Narumi_MAP2K2_AJMG_2007). This variant is also reported as a somatic change in multiple types of cancer, including melanoma (Chang_NatBiotech_2016, Trunzer_JofClinOnc_2013). In the zebrafish embryonic assay the variant was causing dysmorphology and increased embryonic lethality. In addition, other alteration of the same codon, c.371C>A (P124Q) have been reported as a de novo change in CFC patient (Gripp, 2007). Lastly, one clinical diagnostic laboratory and a literature review via ClinVar classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx	RCV000680623	SCV000808065	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Functional studies examining the morphological effect of P124L in zebrafish show a significant effect on oval shape, lethality, and heart size (PMID: 28049852); Published functional studies demonstrate a damaging effect with increased phosphorylation of ERK (PMID: 19915144); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (PMID: 29493581); This variant is associated with the following publications: (PMID: 34522120, 34758253, 17366577, 24803665, 28191890, 28714951, 31785789, 32641410, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 36442478, 28049852, 19915144, 27862862)
CeGaT Center for Human Genetics Tuebingen	RCV000680623	SCV001961515	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813306	SCV002060963	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001542689	SCV002579207	pathogenic	Cardiofaciocutaneous syndrome 3	2022-06-13	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV001542689	SCV002764780	pathogenic	Cardiofaciocutaneous syndrome 3	2022-08-09	criteria provided, single submitter	clinical testing
Invitae	RCV002513329	SCV003442956	pathogenic	RASopathy	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 124 of the MAP2K1 protein (p.Pro124Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MAP2K1-related conditions (PMID: 17366577, 27862862; Invitae). ClinVar contains an entry for this variant (Variation ID: 40744). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MAP2K1 function (PMID: 28049852). This variant disrupts the p.Pro124 amino acid residue in MAP2K1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17551924, 28049852, 32005694, 32978145). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Database of Curated Mutations (DoCM)	RCV000425638	SCV000504547	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436322	SCV000504548	pathogenic	Melanoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417448	SCV000504549	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424633	SCV000504550	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435315	SCV000504551	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542689	SCV001760350	pathogenic	Cardiofaciocutaneous syndrome 3		no assertion criteria provided	clinical testing
GenomeConnect - CFC International	RCV001542689	SCV002047448	not provided	Cardiofaciocutaneous syndrome 3		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-24-2020 by lab or GTR ID Mendelics. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.