NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg) AND Cardio-facio-cutaneous syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: May 9, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000522848.7

Allele description [Variation Report for NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)]

NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)

Gene:

MAP2K1:mitogen-activated protein kinase kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.31

Genomic location:

Preferred name:

NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)

Other names:

p.L92R:CTG>CGG; NM_002755.3(MAP2K1):c.275T>G

HGVS:

NC_000015.10:g.66435221T>G
NG_008305.1:g.53349T>G
NM_002755.4:c.275T>GMANE SELECT
NP_002746.1:p.Leu92Arg
NP_002746.1:p.Leu92Arg
LRG_725t1:c.275T>G
LRG_725:g.53349T>G
LRG_725p1:p.Leu92Arg
NC_000015.9:g.66727559T>G
NM_002755.3:c.275T>G
c.275T>G

Protein change:

L92R

Links:

dbSNP: rs397516791

NCBI 1000 Genomes Browser:

rs397516791

Molecular consequence:

NM_002755.4:c.275T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardio-facio-cutaneous syndrome
Synonyms:: Cardiofaciocutaneous syndrome; CFC syndrome
Identifiers:: MONDO: MONDO:0015280; MedGen: C1275081; Orphanet: 1340; OMIM: PS115150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061251	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000616534	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Likely pathogenic (May 9, 2017)	germline	curation	Citation Link,
SCV000965969	Service de Génétique Moléculaire, Hôpital Robert Debré	no assertion criteria provided	Likely pathogenic	de novo	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061251

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 11, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000616534

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Likely pathogenic
(May 9, 2017)

germline

curation

Citation Link,

SCV000965969

Service de Génétique Moléculaire, Hôpital Robert Debré

no assertion criteria provided

Likely pathogenic

de novo

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing, curation
not provided	de novo	yes	not provided	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061251.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616534.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.275T>G p.Leu92Arg variant in MAP2K1 has been reported in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, APHP-Robert DebrâˆšÂ© hospital internal data, GTR ID: 28338, 26957; ClinVar SCV000061251.5, SCV000207940.10). The p.Leu92Arg variant has been identified in an independent occurrencee in a patient with a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data, GTR ID: 21766, 26957 ClinVar SCV000061251.5 SCV000207940.10). 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).Computational prediction tools and conservation analysis suggest that the p.Leu92Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Supporting, PM2, PP3, PP2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Service de Génétique Moléculaire, Hôpital Robert Debré, SCV000965969.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	1	not provided

Last Updated: Jun 23, 2024

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