NM_005921.2(MAP3K1):c.556A>G (p.Arg186Gly) AND 46,XY sex reversal 6

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 24, 2018
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:: RCV000804251.7

Allele description

NM_005921.2(MAP3K1):c.556A>G (p.Arg186Gly)

Gene:

MAP3K1:mitogen-activated protein kinase kinase kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q11.2

Genomic location:

Preferred name:

NM_005921.2(MAP3K1):c.556A>G (p.Arg186Gly)

HGVS:

NC_000005.10:g.56856673A>G
NG_031884.1:g.46601A>G
NM_005921.2:c.556A>GMANE SELECT
NP_005912.1:p.Arg186Gly
NC_000005.9:g.56152500A>G
NM_005921.1:c.556A>G

Protein change:

R186G

Links:

dbSNP: rs1579750361

NCBI 1000 Genomes Browser:

rs1579750361

Molecular consequence:

NM_005921.2:c.556A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: 46,XY sex reversal 6
Synonyms:: 46,XY SEX REVERSAL, PARTIAL OR COMPLETE, MAP3K1-RELATED; 46,XY GONADAL DYSGENESIS, PARTIAL OR COMPLETE, MAP3K1-RELATED
Identifiers:: MONDO: MONDO:0013410; MedGen: C3151064; OMIM: 613762

Recent activity

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alkaline ceramidase 1 isoform X1 [Homo sapiens]
alkaline ceramidase 1 isoform X1 [Homo sapiens]
gi|768000778|ref|XP_011525975.1|

Protein
GPL32911[Accession] (4)
GEO DataSets
Kidney Epithelioid Angiomyolipoma
Kidney Epithelioid Angiomyolipoma

MedGen
Hyperimmunoglobulin M syndrome
Hyperimmunoglobulin M syndrome

MedGen
Combined immunodeficiency due to partial RAG1 deficiency
Combined immunodeficiency due to partial RAG1 deficiency

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000944151	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 24, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001737544	Cell and Gene Engineering Laboratory, Zhejiang University	no assertion criteria provided	Pathogenic (Nov 7, 2019)	maternal	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000944151

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 24, 2018)

germline

clinical testing

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

SCV001737544

Cell and Gene Engineering Laboratory, Zhejiang University

no assertion criteria provided

Pathogenic
(Nov 7, 2019)

maternal

clinical testing

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
yellow race	maternal	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000944151.4

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

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual affected with¬†46,XY disorder of sexual development¬†(Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 186 of the MAP3K1 protein (p.Arg186Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.

#	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 Cell and Gene Engineering Laboratory, Zhejiang University, SCV001737544.1

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

Description

The Ary186Gly variant in MAP3K1 gene was confirmed by WES and sanger sequencing

Description

The Arg186Gly variant in MAP3K1 has been reported in a girl with 46,XY complete gonadal dysgenesis in our studies which is being submitting. Additionally, in vitro functional studies indicated that the Arg186Gly variant activates ovarian-specific pathways and inhibits testicular-specific pathways. In summary, this results indicates classification of this variant as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	no	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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