rs61751440

Variant names:

• chrX-154030918-T-C
• rs61751440
• NM_001110792.2:c.946A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154030918-T-C
• chrX-154030918-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3_Supporting PP3 PM2_Supporting PS4_Supporting PM5_Strong

This summary comes from the ClinGen Evidence Repository: The p.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong). The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Lys304Glu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PS3_supporting, PS4_supporting, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270580/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.24
• Publications: 8 publications found

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.946A>G	p.Lys316Glu	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.910A>G	p.Lys304Glu	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.631A>G	p.Lys211Glu	missense	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.946A>G	p.Lys316Glu	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.910A>G	p.Lys304Glu	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.910A>G	p.Lys304Glu	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Oct 11, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong). The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Lys304Glu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PS3_supporting, PS4_supporting, PM2_supporting, PP3).

Sep 25, 2023

Centre for Population Genomics, CPG

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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 2.0, this variant is classified as likely pathogenic. At least the following criteria are met: ≥2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact (REVEL score >=0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). Has been observed in in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting).

Jan 21, 2008

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

not provided Pathogenic:1

Apr 22, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate K304E impacts the binding ability of MECP2 (Lyst et al., 2013); Multiple pathogenic missense variants at this residue (p.K304Q and p.K304T) have been reported in association with Rett syndrome (Charman et al., 2005; Lindy et al., 2018); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28348241, 24970834, 16473305, 23770565)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.22	N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.64
MutPred		0.86		Loss of methylation at K304 (P = 0.0025)
MVP		1.0
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.99
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61751440; hg19: chrX-153296369;