NM_001110792.2(MECP2):c.554C>G (p.Pro185Arg) AND Severe neonatal-onset encephalopathy with microcephaly

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 5, 2020
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:: RCV000686598.7

Allele description [Variation Report for NM_001110792.2(MECP2):c.554C>G (p.Pro185Arg)]

NM_001110792.2(MECP2):c.554C>G (p.Pro185Arg)

Gene:

MECP2:methyl-CpG binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001110792.2(MECP2):c.554C>G (p.Pro185Arg)

Other names:

NM_001110792.2(MECP2):c.554C>G; p.Pro185Arg

HGVS:

NC_000023.11:g.154031310G>C
NG_007107.3:g.110794C>G
NM_001110792.2:c.554C>GMANE SELECT
NM_001316337.2:c.239C>G
NM_001369391.2:c.239C>G
NM_001369392.2:c.239C>G
NM_001369393.2:c.239C>G
NM_001369394.2:c.239C>G
NM_001386137.1:c.-128-24C>G
NM_001386138.1:c.-128-24C>G
NM_001386139.1:c.-128-24C>G
NM_004992.4:c.518C>G
NP_001104262.1:p.Pro185Arg
NP_001303266.1:p.Pro80Arg
NP_001356320.1:p.Pro80Arg
NP_001356321.1:p.Pro80Arg
NP_001356322.1:p.Pro80Arg
NP_001356323.1:p.Pro80Arg
NP_004983.1:p.Pro173Arg
NP_004983.1:p.Pro173Arg
LRG_764t1:c.554C>G
LRG_764t2:c.518C>G
AJ132917.1:c.518C>G
LRG_764:g.110794C>G
LRG_764p1:p.Pro185Arg
LRG_764p2:p.Pro173Arg
NC_000023.10:g.153296761G>C
NG_007107.2:g.110818C>G
NM_004992.3:c.518C>G

Protein change:

P173R

Links:

dbSNP: rs267608492

NCBI 1000 Genomes Browser:

rs267608492

Molecular consequence:

NM_001386137.1:c.-128-24C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001386138.1:c.-128-24C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001386139.1:c.-128-24C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001110792.2:c.554C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.239C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.239C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.239C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.239C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.239C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.518C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Severe neonatal-onset encephalopathy with microcephaly
Synonyms:: Encephalopathy, neonatal severe; Encephalopathy, neonatal severe, due to MECP2 mutations
Identifiers:: MONDO: MONDO:0010397; MedGen: C1968556; Orphanet: 209370; OMIM: 300673

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000814123	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 5, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23696494, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000814123

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 5, 2020)

germline

clinical testing

PubMed (2)
[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

Detection of rarely identified multiple mutations in MECP2 gene do not contribute to enhanced severity in Rett syndrome.

Chapleau CA, Lane J, Kirwin SM, Schanen C, Vinette KM, Stubbolo D, MacLeod P, Glaze DG, Motil KJ, Neul JL, Skinner SA, Kaufmann WE, Percy AK.

Am J Med Genet A. 2013 Jul;161A(7):1638-46. doi: 10.1002/ajmg.a.35979. Epub 2013 May 21. Erratum in: Am J Med Genet A. 2014 May;164A(5):1346. Glaze, Daniel G [added]; Motil, Kathleen J [added]; Neul, Jeffrey L [added]; Skinner, Steven A [added]; Kaufmann, Walter E [added].

PubMed [citation]

PMID:: 23696494
PMCID:: PMC3689857

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000814123.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual with Rett syndrome as inherited from an unaffected mother with random X-chromosome inactivation, however, that individual also carried another variant that was de novo and in trans(on the opposite chromosome) with this variant (PMID: 23696494). ClinVar contains an entry for this variant (Variation ID: 143609). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 173 of the MECP2 protein (p.Pro173Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine.

#	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: Oct 8, 2024

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