rs28935168

chrX-154032286-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):c.334C>G(p.Leu112Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L112R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 5.39

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-154032286-G-C is Pathogenic according to our data. Variant chrX-154032286-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 11835.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154032286-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.334C>G	p.Leu112Val	missense_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4	c.298C>G	p.Leu100Val	missense_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.334C>G	p.Leu112Val	missense_variant	2/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.298C>G	p.Leu100Val	missense_variant	3/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Uncertain significance, no assertion criteria provided	curation	RettBASE	Sep 27, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2003	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	May 10, 2022	The p.Leu100Val (NM_004992) variant has been observed in at least 5 other individuals with Rett Syndrome (PMID: 22476991, 16672765, 12966522, 11913567, 11055898, RettBASE) (PS4). The p.Leu100Val variant occurs in the well-characterized Methyl-DNA binding [MBD] functional domain of the MECP2 (PM1). The p.Leu100Val variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Leu100Val variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with mild atypical Rett syndrome (PMID: 12966522)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu100Val variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PP3). -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 2024	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 pathogenic. At least the following criteria are met: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 22476991, 16672765, 12966522, 11913567, 11055898, ClinVar Variation ID: 11835 Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 12966522) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 22476991 This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	Published functional studies demonstrate that this variant leads to an unstable MECP2 protein (Kucukkal et al., 2015; Yang et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12966522, 16672765, 21831886, 12843318, 28351539, 26239053, 27356039, 11055898, 22476991, 32472557, 11913567, 26418480, 12673788) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;T;D;D;T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N;N;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Benign	0.043	D;D;.;.;.;.;.
Sift4G	Benign	0.20	T;T;D;D;.;D;D
Polyphen		0.98	D;D;.;.;.;.;.
Vest4		0.86
MutPred		0.91		Gain of MoRF binding (P = 0.0927);.;Gain of MoRF binding (P = 0.0927);.;Gain of MoRF binding (P = 0.0927);.;.;
MVP		1.0
ClinPred		0.86	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs28935168; hg19: chrX-153297737;