NM_001110792.2(MECP2):c.737C>T (p.Ala246Val) AND Severe neonatal-onset encephalopathy with microcephaly

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 17, 2017
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:: RCV000645116.7

Allele description [Variation Report for NM_001110792.2(MECP2):c.737C>T (p.Ala246Val)]

NM_001110792.2(MECP2):c.737C>T (p.Ala246Val)

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.737C>T (p.Ala246Val)

HGVS:

NC_000023.11:g.154031127G>A
NG_007107.3:g.110977C>T
NM_001110792.2:c.737C>TMANE SELECT
NM_001316337.2:c.422C>T
NM_001369391.2:c.422C>T
NM_001369392.2:c.422C>T
NM_001369393.2:c.422C>T
NM_001369394.2:c.422C>T
NM_001386137.1:c.32C>T
NM_001386138.1:c.32C>T
NM_001386139.1:c.32C>T
NM_004992.4:c.701C>T
NP_001104262.1:p.Ala246Val
NP_001303266.1:p.Ala141Val
NP_001356320.1:p.Ala141Val
NP_001356321.1:p.Ala141Val
NP_001356322.1:p.Ala141Val
NP_001356323.1:p.Ala141Val
NP_001373066.1:p.Ala11Val
NP_001373067.1:p.Ala11Val
NP_001373068.1:p.Ala11Val
NP_004983.1:p.Ala234Val
NP_004983.1:p.Ala234Val
LRG_764t1:c.737C>T
LRG_764t2:c.701C>T
LRG_764:g.110977C>T
LRG_764p1:p.Ala246Val
LRG_764p2:p.Ala234Val
NC_000023.10:g.153296578G>A
NG_007107.2:g.111001C>T
NM_004992.3:c.701C>T

Protein change:

A11V

Links:

dbSNP: rs138211345

NCBI 1000 Genomes Browser:

rs138211345

Molecular consequence:

NM_001110792.2:c.737C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386137.1:c.32C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386138.1:c.32C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386139.1:c.32C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.701C>T - 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
SCV000766858	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 17, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000766858

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 17, 2017)

germline

clinical testing

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

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

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, SCV000766858.4

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

Description

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. 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 missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MECP2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 234 of the MECP2 protein (p.Ala234Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine.

#	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: Sep 29, 2024

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