MECP2 p.Thr170Met

Variant names:

• chrX-154031355-G-A
• rs28934906
• NM_001110792.2:c.509C>T
• MECP2 p.Thr170Met

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 18 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Strong

The NM_001110792.2(MECP2):c.509C>T (p.Thr170Met) variant causes a missense change involving the alteration of a 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. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.45). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002073016: Functional studies have shown a damaging effect (Brown K et al., 2016)." 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.T170K: Likely_pathogenic (ClinVar VariationId 1501953, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T170= (synonymous): Likely_benign (ClinVar VariationId 2012560, 1 star); p.T170= (synonymous): Benign/Likely_benign (ClinVar VariationId 143591, 2 stars) 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:60 O:1
• Conservation: PhyloP100: 9.45
• Publications: 366 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, PanelApp Australia
• 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

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.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV002073016: Functional studies have shown a damaging effect (Brown K et al., 2016).; SCV003845196: Experimental studies have shown that this missense change affects MECP2 protein function by Ballestar, Esteban, Timur M. Yusufzai, and Alan P. Wolffe., 2000.; SCV000191038: "In vitro functional studies indicate that T158M impairs normal protein function (Yusufzai et al., 2000; Kudo et al., 2003; Agarwal et al., 2011; Lyst et al., 2013; Sheikh et al., 2016)"; SCV005849335: Experimental studies have shown that this missense change affects MECP2 function (Yusufzai TM et al. 2000).; SCV000645667: Experimental studies have shown that this missense change affects MECP2 function (PMID: 10852707, 11058114, 11738866, 12843318, 21831886, 26647311).; SCV000845943: Functional analysis demonstrated that the p.T158M alteration moderately affects MeCP2's ability to bind to methylated DNA and impair selectivity for methylated DNA (Ballestar, 2000; Yusufzai, 2000).; SCV003920187: In addition, in vivo functional studies support a deleterious effect of this variant, suggesting impaired binding stability and selectivity for methylated DNA (Yusufzai 2000 PMID:11058114, Bao 2013 PMID:23421866).; SCV005418096: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV004814138: "The c.509C>T variant disrupts hydrogen bonding in a critical region of the C-terminal end of the methyl-DNA binding region (MDB), a well-established functional domain, which leads to compromised binding to methylated DNA and affects stability (Brown et al. 2016)."; SCV005358263: Functional analysis has indicated that this variant impairs DNA binding affinity (Kucukkal et al. 2015. PubMed ID: 26418480; Yusufzai and Wolffe. 2000. PubMed ID: 11058114).
	PM1Mutational hot spot or critical domain		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: 27 pathogenic, 1 benign (OR vs. background: 91.7).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		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.T170K: Likely_pathogenic (ClinVar VariationId 1501953, 1 star); Other variants at the same amino acid residue (not pathogenic): p.T170= (synonymous): Likely_benign (ClinVar VariationId 2012560, 1 star); p.T170= (synonymous): Benign/Likely_benign (ClinVar VariationId 143591, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (60/60 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.509C>T p.Thr170Met	missense	Exon 3 of 3	Prot: NP_001104262.1 UniProt:
	MECP2 NM_004992.4	MANE Plus Clinical	c.473C>T p.Thr158Met	missense	Exon 4 of 4	Prot: NP_004983.1 UniProt:
	MECP2 NM_001316337.2		c.194C>T p.Thr65Met	missense	Exon 5 of 5	Prot: NP_001303266.1

MECP2 NM_001110792.2

MANE Select

HGVSc / HGVSpc.509C>Tp.Thr170Met

Exon rankExon 3 of 3

missense

Prot: NP_001104262.1UniProt: A0A140VKC4P51608-2

MECP2 NM_004992.4

MANE Plus Clinical

HGVSc / HGVSpc.473C>Tp.Thr158Met

Exon rankExon 4 of 4

missense

Prot: NP_004983.1UniProt: D3YJ43P51608-1

MECP2 NM_001316337.2

HGVSc / HGVSpc.194C>Tp.Thr65Met

Exon rankExon 5 of 5

missense

Prot: NP_001303266.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MECP2 ENST00000453960.7	TSL:1MANE Select	c.509C>T p.Thr170Met	missense	Exon 3 of 3	Prot: ENSP00000395535.2 UniProt:
	MECP2 ENST00000303391.11	TSL:1MANE Plus Clinical	c.473C>T p.Thr158Met	missense	Exon 4 of 4	Prot: ENSP00000301948.6 UniProt:
	MECP2 ENST00000630151.3	TSL:5	c.473C>T p.Thr158Met	missense	Exon 4 of 4	Prot: ENSP00000486089.2 UniProt:

MECP2 ENST00000453960.7

TSL:1MANE Select

HGVSc / HGVSpc.509C>Tp.Thr170Met

Exon rankExon 3 of 3

missense

Prot: ENSP00000395535.2UniProt: P51608-2

MECP2 ENST00000303391.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.473C>Tp.Thr158Met

Exon rankExon 4 of 4

missense

Prot: ENSP00000301948.6UniProt: P51608-1

MECP2 ENST00000630151.3

TSL:5

HGVSc / HGVSpc.473C>Tp.Thr158Met

Exon rankExon 4 of 4

missense

Prot: ENSP00000486089.2UniProt: A0A0D9SEX1P51608-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000399	AC:1	Hom:0	AN:25090	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
28	-	-	Rett syndrome (29)
15	-	-	not provided (15)
4	-	-	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 (4)
3	-	-	Severe neonatal-onset encephalopathy with microcephaly (3)
2	-	-	Autism, susceptibility to, X-linked 3 (2)
2	-	-	MECP2-related disorder (2)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Angelman syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	Syndromic X-linked intellectual disability Lubs type (1)
1	-	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-8.8
GPN-Star score	N/A	8.8
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	11/89	disease causing (ClinVar)
MutationAssessor	Benign	1.8	L
PhyloP100	Pathogenic	9.5
popEVE	Benign	-4.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.3	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Varity_R	N/A	0.91
VESM-3B	Benign	-11

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28934906;

hg19: chrX-153296806;

COSMIC: COSV57651729;

COSMIC: COSV57651729;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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