rs28935468

Variant names:

• chrX-154030912-G-A
• rs28935468
• NM_001110792.2:c.952C>T
• MECP2 p.Arg318Cys

GermlineCancer (beta)

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 20 classification points (ACMG Germline Pathogenicity v2019): 20P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001110792.2(MECP2):c.952C>T (p.Arg318Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000698547: Functional studies showed that this variant decreased microtubule (MT) stability and down-regulated GRID1, a gene in the neurotransmitter pathway which is known to be down-regulated in the absence of functional MECP2 (Delepine_FEBSL_2013, Livide_EJHG_2014)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R318H: Pathogenic/Likely_pathogenic (ClinVar VariationId 143746, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R318= (synonymous): Likely_benign (ClinVar VariationId 1127365, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Rett syndrome (rtt); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:50 O:1
• Conservation: PhyloP100: 7.09
• Publications: 114 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):

• Rett syndrome

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

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000698547: Functional studies showed that this variant decreased microtubule (MT) stability and down-regulated GRID1, a gene in the neurotransmitter pathway which is known to be down-regulated in the absence of functional MECP2 (Delepine_FEBSL_2013, Livide_EJHG_2014).; SCV001445896: Functional studies have shown this missense variant disrupts the ability of the MeCP2 protein to associate with co-repressors (PMID: 23770587, 23770565, 24970834), impairs DNA-binding in vivo and in vitro (PMID: 26647311, 11058114), and results in decreased microtubule stability (PMID: 23238081).; SCV002820191: Experimental studies have shown that this missense change abolishes the interaction between MECP2 and its co-repressor and impairs DNA-binding both in vitro and in vivo (Lyst et al, 2013; Heckman et al. 2014).; SCV004801532: Functional studies in patient fibroblasts and cultured cortical neurons, demonstrated that the p.(Arg306Cys) variant protein resulted in almost total depolymerization of microtubules under the effect of cold-induced stress and also rendered the variant protein incapable of interacting with the nuclear receptor co-repressor complex as compared with wildtype protein (Delépine et al. 2013; Ebert et al. 2013).; SCV005088818: The variant occurs in the well-characterized transcriptional repression domain (TRD) the functional domain of MECP2 and experimental studies have shown that this variant affects MECP2 function [PMID: 23770565, 23770587, 24970834, 26647311].; SCV000190987: Published functional studies demonstrate that the R306C variant results in a damaging effect (Heckman et al., 2014; Kruusvee et al., 2017); SCV000884099: Functional characterization of the MECP2 variant protein indicates disruption in its association with co-repressors, such as HDAC3 and the NCoR complex (Ebert 2013, Heckman 2014, Lyst 2013), and reduction in in-vivo DNA occupancy (Heckman 2014). PMID: 23770587, PMID: 24970834, PMID: 23770565; SCV002774385: In addition, functional studies report this variant is damaging to MECP2 protein function (PMIDs: 23770565 (2013), 23770587 (2013), 24970834 (2014), and 26647311 (2016)).; SCV004229773: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23770565, 24970834, 23770587, 26647311); SCV000544613: Experimental studies have shown that this missense change affects MECP2 function (PMID: 23770565, 23770587, 24970834, 26647311).; SCV002683250: Functional studies demonstrated that this alteration had decreased microtubule stability, abolished the interaction of MeCP2 with the NCoR/SMRT co-repressor, and down regulated GRID1 expression (Delépine, 2013; Lyst, 2013; Livide, 2015).; SCV003920185: Both in vitro and in vivo functional studies have shown a deleterious effect for this variant (Delepine 2013 PMID: 23238081; Ebert 2013 PMID: 23770587; Lyst 2013 PMID: 23770656; Heckman 2014 PMID: 24970834; Livide 2015 PMID: 24970834; Brown 2016 PMID: 26647311).; SCV004745453: pathogenicity of this recurrent variant is supported by functional studies, as well as its presence in numerous affected individuals (Brown et al. 2016. PubMed ID: 26647311).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 25 pathogenic, 2 benign (OR vs. background: 51.0).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R318H: Pathogenic/Likely_pathogenic (ClinVar VariationId 143746, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R318= (synonymous): Likely_benign (ClinVar VariationId 1127365, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (50/50 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.952C>T	p.Arg318Cys	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.916C>T	p.Arg306Cys	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.637C>T	p.Arg213Cys	missense	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.952C>T	p.Arg318Cys	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.916C>T	p.Arg306Cys	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.916C>T	p.Arg306Cys	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
25	-	-	Rett syndrome (26)
16	-	-	not provided (16)
1	-	-	Angelman syndrome (1)
1	-	-	Autism, susceptibility to, X-linked 3 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	MECP2-related disorder (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (1)
1	-	-	See cases (1)
1	-	-	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.55	D
PhyloP100		7.1
Sift4G	Benign	0.17	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
Mutation Taster		=5/95	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28935468;

hg19: chrX-153296363;

COSMIC: COSV100318414;

COSMIC: COSV100318414;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar