NM_002755.4(MAP2K1):c.175_177del (p.Lys59del) AND RASopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002515536.4

Allele description [Variation Report for NM_002755.4(MAP2K1):c.175_177del (p.Lys59del)]

NM_002755.4(MAP2K1):c.175_177del (p.Lys59del)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

15q22.31

Genomic location:

Preferred name:

NM_002755.4(MAP2K1):c.175_177del (p.Lys59del)

HGVS:

NC_000015.10:g.66435121_66435123del
NG_008305.1:g.53249_53251del
NM_002755.3:c.175_177del
NM_002755.4:c.175_177delMANE SELECT
NP_002746.1:p.Lys59del
LRG_725t1:c.175_177del
LRG_725:g.53249_53251del
NC_000015.9:g.66727457_66727459del
NC_000015.9:g.66727459_66727461del
NM_002755.3:c.175_177delAAG

Protein change:

K59del

Links:

OMIM: 176872.0004; dbSNP: rs869025339

NCBI 1000 Genomes Browser:

rs869025339

Molecular consequence:

NM_002755.4:c.175_177del - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003442955	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17551924, 29753091, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003442955

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 2, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.

Gripp KW, Lin AE, Nicholson L, Allen W, Cramer A, Jones KL, Kutz W, Peck D, Rebolledo MA, Wheeler PG, Wilson W, Al-Rahawan MM, Stabley DL, Sol-Church K.

Am J Med Genet A. 2007 Jul 1;143A(13):1472-80.

PubMed [citation]

PMID:: 17551924

Increase in constitutively active MEK1 species by introduction of MEK1 mutations identified in cancers.

Kinoshita-Kikuta E, Kinoshita E, Ueda S, Ino Y, Kimura Y, Hirano H, Koike T.

Biochim Biophys Acta Proteins Proteom. 2019 Jan;1867(1):62-70. doi: 10.1016/j.bbapap.2018.05.004. Epub 2018 May 9.

PubMed [citation]

PMID:: 29753091

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442955.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant, c.175_177del, results in the deletion of 1 amino acid(s) of the MAP2K1 protein (p.Lys59del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 17551924). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 222074). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MAP2K1 function (PMID: 29753091).

#	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

Last Updated: Apr 13, 2025

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