rs61751450

Positions:

• chrX-154030863-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4 PM2_Supporting PM6_Strong PS4 PM5

This summary comes from the ClinGen Evidence Repository: The c.965C>T p.(Pro322Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro322Leu) variant has been observed in at least 5 individuals with Rett syndrome (PMID:10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PS4, PP4), where it has been reported in as de novo occurrences (biological parentage unconfirmed) in at least 2 individuals (PMID 10814718, 11402105) (PM6_strong). Multiple missense variants have been previously identified within this codon, at least one of which is classified as pathogenic; this indicates that this residue is critical to the function of the protein (PMID 10814719, 16966553, 16225173, 32820509) (PM5). In summary, the c.965C>T p.(Pro322Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PP4, PM5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270591/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: 4.58

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 12 ACMG points.

• 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.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1001C>T	p.Pro334Leu	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.965C>T	p.Pro322Leu	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1001C>T	p.Pro334Leu	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.965C>T	p.Pro322Leu	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jul 05, 2022	The c.965C>T p.(Pro322Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro322Leu) variant has been observed in at least 5 individuals with Rett syndrome (PMID: 10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PS4, PP4), where it has been reported in as de novo occurrences (biological parentage unconfirmed) in at least 2 individuals (PMID 10814718, 11402105) (PM6_strong). Multiple missense variants have been previously identified within this codon, at least one of which is classified as pathogenic; this indicates that this residue is critical to the function of the protein (PMID 10814719, 16966553, 16225173, 32820509) (PM5). In summary, the c.965C>T p.(Pro322Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PP4, PM5). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Aug 24, 2010	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 08, 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: This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID: 17089071, PMID 10814718, 11402105) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 35010767, 35712450, 17089071, 16473305, 15526954, 34126956, 10814718, 12075494, 24623853, 26457613, 19194883, 16672765, 32370253,ClinVar Variation ID: 143754) This variant is absent from gnomAD (PM2_Supporting). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MECP2 protein function (PMID: 29718204). This variant has been observed in individual(s) with Rett syndrome (PMID: 17089071, 15526954, 10814718). ClinVar contains an entry for this variant (Variation ID: 143754). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 322 of the MECP2 protein (p.Pro322Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2017

The P322L pathogenic variant in the MECP2 gene is a recurrent variant reported in cohorts of individuals diagnosed with Rett syndrome (Lima et al., 2009; Kim et al., 2006; Philippe et al., 2006; Hoffbuhr et al., 2001) and has been reported specifically in a female who exhibited severe Rett syndrome clinical features (Huppke et al., 2000). The P322L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P322L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Lab, CHRU Brest

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.43	B;P
Vest4		0.30
MutPred		0.88		Loss of sheet (P = 0.0104);.;
MVP		1.0
ClinPred		0.85	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.88

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: rs61751450; hg19: chrX-153296314; COSMIC: COSV57654028; COSMIC: COSV57654028;