NM_001110792.2(MECP2):c.251C>T (p.Pro84Leu) AND Rett syndrome

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Oct 26, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001800450.5

Allele description [Variation Report for NM_001110792.2(MECP2):c.251C>T (p.Pro84Leu)]

NM_001110792.2(MECP2):c.251C>T (p.Pro84Leu)

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.251C>T (p.Pro84Leu)

Other names:

NM_001110792.2(MECP2):c.251C>T; p.Pro84Leu

HGVS:

NC_000023.11:g.154032369G>A
NG_007107.3:g.109735C>T
NM_001110792.2:c.251C>TMANE SELECT
NM_001316337.2:c.-65C>T
NM_001369391.2:c.-65C>T
NM_001369392.2:c.-65C>T
NM_001369393.2:c.-65C>T
NM_001369394.2:c.-65C>T
NM_001386137.1:c.-346C>T
NM_001386138.1:c.-346C>T
NM_001386139.1:c.-346C>T
NM_004992.4:c.215C>T
NP_001104262.1:p.Pro84Leu
NP_004983.1:p.Pro72Leu
NP_004983.1:p.Pro72Leu
LRG_764t1:c.251C>T
LRG_764t2:c.215C>T
AJ132917.1:c.215C>T
LRG_764:g.109735C>T
LRG_764p1:p.Pro84Leu
LRG_764p2:p.Pro72Leu
NC_000023.10:g.153297820G>A
NG_007107.2:g.109759C>T
NM_004992.3:c.215C>T

Protein change:

P72L

Links:

dbSNP: rs61754440

NCBI 1000 Genomes Browser:

rs61754440

Molecular consequence:

NM_001316337.2:c.-65C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369391.2:c.-65C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369392.2:c.-65C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369393.2:c.-65C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369394.2:c.-65C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386137.1:c.-346C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-346C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-346C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.251C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Rett syndrome (RTT)
Synonyms:: Autism, dementia, ataxia, and loss of purposeful hand use; Rett's disorder
Identifiers:: MONDO: MONDO:0010726; MedGen: C0035372; Orphanet: 3095; Orphanet: 778; OMIM: 312750

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002047357	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Likely benign (Oct 26, 2021)	germline	curation	Citation Link,
SCV004808859	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Likely benign (Mar 20, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002047357

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)

Likely benign
(Oct 26, 2021)

germline

curation

Citation Link,

SCV004808859

Centre for Population Genomics, CPG

criteria provided, single submitter

(McKnight et al. (Hum Mutat. 2022))

Likely benign
(Mar 20, 2024)

germline

curation

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

Citation Link

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	curation

Citations

PubMed

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.

McKnight D, Bean L, Karbassi I, Beattie K, Bienvenu T, Bonin H, Fang P, Chrisodoulou J, Friez M, Helgeson M, Krishnaraj R, Meng L, Mighion L, Neul J, Percy A, Ramsden S, Zoghbi H, Das S.

Hum Mutat. 2022 Aug;43(8):1097-1113. doi: 10.1002/humu.24302. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 34837432
PMCID:: PMC9135956

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002047357.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The allele frequency of the p.Pro72Leu variant in MECP2 (NM_004992.3) is 0.01338% in the Ashkenazi Jewish sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro72Leu variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro72Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting).

#	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 Centre for Population Genomics, CPG, SCV004808859.1

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

Description

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v2 is between 0.008% and 0.03% (BS1).

#	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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