Submissions for variant NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)

dbSNP: rs121908595

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000208757	SCV000616532	pathogenic	Cardio-facio-cutaneous syndrome	2017-05-09	reviewed by expert panel	curation	The c.389A>G (p.Tyr130Cys) variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStong; PMID 16439621, 17551924, 18042262). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr130Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PP3, PS3, PM2, PP2, PM1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208757	SCV000061256	pathogenic	Cardio-facio-cutaneous syndrome	2016-08-30	criteria provided, single submitter	clinical testing	The p.Tyr130Cys variant in MAP2K1 has been reported in >15 individuals with clin ical features of Cardio-facio-cutaneous (CFC) syndrome and occurred de novo in a t least 10 individuals (Rodriguez-Viciana 2006, Gripp 2007, Narumi 2007, Schulz 2008, Dentici 2009, LMM data). This variant was absent from large population stu dies. In vitro functional studies provide some evidence that this variant may im pact protein function (Rodriguez-Viciana 2006). Computational prediction tools a nd conservation analysis suggest that the p.Tyr130Cys variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, this variant meets criteria to be classified as pathogenic for CF C in an autosomal dominant manner based on multiple de novo occurrences and abse nce from controls.
GeneDx	RCV000207506	SCV000207943	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect in which the variant causes increased kinase activity and activation of downstream effectors (MEK and ERK), indicating a gain of function (Rodriguez-Viciana et al., 2008); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 26607044, 26922062, 18413255, 16439621, 24637312, 18042262, 19156172, 26350204, 26795593, 28049852, 24803665, 27862862, 17567882, 30050098, 31972311, 31057598, 29907801, 31618753, 32369273, 32866538, 17551924, 17981815, 33673806, 33482860, 32335888)
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000043672	SCV000236502	pathogenic	Cardiofaciocutaneous syndrome 3	2013-12-20	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207506	SCV000263049	pathogenic	not provided	2015-07-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000207506	SCV000341853	pathogenic	not provided	2016-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541525	SCV000659027	pathogenic	RASopathy	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 130 of the MAP2K1 protein (p.Tyr130Cys). This variant is present in population databases (rs121908595, gnomAD 0.0009%). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16439621, 17366577, 17551924, 18413255, 18854871, 24637312, 26350204, 26795593). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13351). 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 have shown that this missense change affects MAP2K1 function (PMID: 16439621, 18413255, 19376813). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208757	SCV000698036	pathogenic	Cardio-facio-cutaneous syndrome	2016-04-26	criteria provided, single submitter	clinical testing	Variant summary: The c.389A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant. This variant is not found in approximately 121830 control chromosomes. The variant has been reported in several CFC patients including multiple confirmed de novo occurrences, a very strong evidence for pathogenic outcome. A functional study by Rodriguez-Viciana et al 2006 also showed the variant to have an activating effect on ERK phosphorylation, consistent with disease mechanism in CFC. Several clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000623321	SCV000740780	pathogenic	Inborn genetic diseases	2015-01-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000043672	SCV000807282	pathogenic	Cardiofaciocutaneous syndrome 3	2023-05-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763362	SCV000894053	pathogenic	Noonan syndrome 1; Cardiofaciocutaneous syndrome 3	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000043672	SCV001150155	pathogenic	Cardiofaciocutaneous syndrome 3	2018-04-11	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197351	SCV001368059	pathogenic	Melorheostosis	2019-05-13	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000207506	SCV001447569	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000043672	SCV001739457	pathogenic	Cardiofaciocutaneous syndrome 3	2020-02-28	criteria provided, single submitter	clinical testing
3billion	RCV000043672	SCV002058534	pathogenic	Cardiofaciocutaneous syndrome 3	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 17551924, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013351, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.977, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Cardiofaciocutaneous syndrome 3 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040747,VCV000636238, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV000043672	SCV002061277	pathogenic	Cardiofaciocutaneous syndrome 3	2022-01-05	criteria provided, single submitter	clinical testing	The c.389A>G;p.(Tyr130Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13351 PMID 16439621; 17551924; 18042262; 18413255; 23093928; 17981815 ) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 18413255, 23093928, 17981815) - PS3. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 16439621; 17551924; 18042262) - PS2.The variant is located in a mutational hot spot and/or critical and well-established functional domain (hot spot region - PMID: 29493581) - PM1. The variant is present at low allele frequencies population databases (rs121908595– gnomAD 0.00003977%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000043672	SCV002577552	pathogenic	Cardiofaciocutaneous syndrome 3	2022-05-09	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000043672	SCV002767402	pathogenic	Cardiofaciocutaneous syndrome 3	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with cardiofaciocutaneous syndrome 3 (MIM#615279). Pathogenic variants display increased phosphorylation of target proteins (OMIM, PMID: 30087384). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The features associated with cardiofaciocutaneous syndrome 3 (MIM#615279), such as the degree of intellectual disability, have been shown to vary widely been reported patients (PMID: 27862862). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated catalytic kinase domain (NCBI). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes at the same residue, to histidine and asparagine, have previously been reported as pathogenic in multiple individuals with cardiofaciocutaneous syndrome 3 (MIM#615279) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been found de novo in multiple individuals with cardiofaciocutaneous syndrome 3 (MIM#615279) and has been classified as pathogenic by an FDA recognised database (ClinVar, DECIPHER, PMID: 27862862). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant has been shown to result in increased intrinsic kinase activity compared to wild-type (PMID: 30087384). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000043672	SCV002820269	pathogenic	Cardiofaciocutaneous syndrome 3	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.389A>G (p.Tyr130Cys) in the MAP2K1 gene has been reported previously in multiple individual(s) with Cardiofaciocutaneous syndrome. Experimental studies have shown that this missense change affects MAP2K1 function (Wang Q, et al., 2020; Cao H, et al., 2022; Al-Rahawan MM, et al., 2007; Anastasaki C, et al., 2009; Cheng TM, et al., 2012). This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters and the ClinGen Rasopathy expert panel. The amino acid Tyrosine at position 130 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000043672	SCV003823479	pathogenic	Cardiofaciocutaneous syndrome 3	2022-10-21	criteria provided, single submitter	clinical testing
OMIM	RCV000043672	SCV000034528	pathogenic	Cardiofaciocutaneous syndrome 3	2007-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000208757	SCV000264638	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	literature only
GenomeConnect - CFC International	RCV000541525	SCV001245247	not provided	RASopathy		no assertion provided	phenotyping only	Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 04-09-2014 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 02-04-2021 by lab or GTR ID Victorian Clinical Genetics Services, Murdoch Children's Research Institute. 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.
Shieh Lab, University of California, San Francisco	RCV000043672	SCV001441642	pathogenic	Cardiofaciocutaneous syndrome 3	2020-10-19	no assertion criteria provided	research
Pediatric Genetics Clinic, Sheba Medical Center	RCV000043672	SCV001712198	pathogenic	Cardiofaciocutaneous syndrome 3	2021-05-13	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000207506	SCV001809617	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000207506	SCV001952154	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000043672	SCV002073950	pathogenic	Cardiofaciocutaneous syndrome 3	2022-02-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532347	SCV004116063	pathogenic	MAP2K1-related disorder	2024-04-29	no assertion criteria provided	clinical testing	The MAP2K1 c.389A>G variant is predicted to result in the amino acid substitution p.Tyr130Cys. This variant has been reported in multiple individuals to be causative for cardio-facio-cutaneous (CFC) Syndrome (e.g., Rodriguez-Viciana et al. 2006. PubMed ID: 16439621; Çelik et al. 2014. PubMed ID: 24637312). In at least some of these individuals, this variant was reported to have arisen de novo (Ziats et al. 2020. PubMed ID: 31618753; Wang et al. 2020. PubMed ID: 32335888; Shieh et al. 2021. PubMed ID: 34556655). Functional studies have shown that this variant disrupts MAP2K1 protein function (Rodriguez-Viciana et al. 2006. PubMed ID: 16439621; Anastasaki et al. 2009. PubMed ID: 19376813). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Molecular Genetics, Centre for Human Genetics	RCV003450638	SCV004190075	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing