rs61748407

Variant names:

• chrX-154031361-T-C
• rs61748407
• NM_001110792.2:c.503A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154031361-T-C
• chrX-154031361-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS3_Supporting PM2 PP3 PM6_Strong PM1 PM5 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Asp156Gly variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with phenotype consistent with Rett syndrome (PMID 11309679, 11241840) (PM6_strong). The p.Asp156Gly variant in MECP2 has been observed in at least 2 other individuals with clinical features of Rett syndrome (PMID 11309679, 11241840) (PS4_moderate). The p.Asp156Gly variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). A pathogenic missense variant (p.Asp156Glu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11524741, 15737703, 26984561, 27354166, 12843318, 26418480, internal database - Invitae) (PM5). The p.Asp156Gly variant in MECP2 is absent from gnomAD (PM2_supporting). Chromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (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.Asp156Gly variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM5, PS3_supporting, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270431/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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.
• PM1: 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.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.503A>G	p.Asp168Gly	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.467A>G	p.Asp156Gly	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.503A>G	p.Asp168Gly	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.467A>G	p.Asp156Gly	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Apr 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MECP2 c.467A>G (p.Asp156Gly) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182743 control chromosomes (gnomAD). c.467A>G has been reported in the literature as a de novo occurrence without confirmation of paternity in at least two individuals affected with Rett Syndrome (e.g. Laccone_2001, Trappe_2001). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant severely reduces heterochromatin binding and impairs transcriptional repression activity versus the WT protein (Kudo_2003). Additionally, another missense variant affecting this amino acid (p.Asp156Glu) has been determined to be pathogenic by our laboratory and others in ClinVar (Variation ID: 95196), suggesting this may be a functionally important residue. The following publications have been ascertained in the context of this evaluation (PMID: 12843318, 11241840, 11309679). ClinVar contains an entry for this variant (Variation ID: 143583). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Asp156Gly variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with phenotype consistent with Rett syndrome (PMID 11309679, 11241840) (PM6_strong). The p.Asp156Gly variant in MECP2 has been observed in at least 2 other individuals with clinical features of Rett syndrome (PMID 11309679, 11241840) (PS4_moderate). The p.Asp156Gly variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). A pathogenic missense variant (p.Asp156Glu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11524741, 15737703, 26984561, 27354166, 12843318, 26418480, internal database - Invitae) (PM5). The p.Asp156Gly variant in MECP2 is absent from gnomAD (PM2_supporting). Chromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (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.Asp156Gly variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM5, PS3_supporting, PM2_supporting, PP3). -

Sep 05, 2002

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Oct 13, 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: This variant has been identified as a de novo occurrence in ≥2 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_strong, PMID: 11309679 PMID: 11241840). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score >=0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

Inborn genetic diseases Pathogenic:1

May 22, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MECP2 c.467A>G (p.Asp156Gly) variant has been reported in the published literature as a de novo in at least two individuals with Rett syndrome (PMIDs: 11241840 (2001) and 11309679 (2001)). Experimental studies suggested that this variant has a damaging on protein function and results in severely impaired chromatin binding and reduced transcriptional repression (PMID: 12843318 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;.;D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.4	D;D;.;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	D;D;.;.;.
Sift4G	Uncertain	0.030	D;D;.;T;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.88
MutPred		0.94		Loss of stability (P = 0.0153);.;Loss of stability (P = 0.0153);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs61748407; hg19: chrX-153296812;