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

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 [Variation Report for NM_005921.2(MAP3K1):c.556A>G (p.Arg186Gly)]

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:
1

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000944151Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Aug 24, 2018)
germlineclinical testing

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

SCV001737544Cell and Gene Engineering Laboratory, Zhejiang University
no assertion criteria provided
Pathogenic
(Nov 7, 2019)
maternalclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
yellow racematernalno1not providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000944151.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1yellow race1not providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalnonot providednot providednot provided1not providednot providednot provided

Last Updated: Feb 20, 2024