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NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs) AND Rett syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jul 21, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000590874.2

Allele description [Variation Report for NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs)]

NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs)

Gene:
MECP2:methyl-CpG binding protein 2 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs)
Other names:
NM_001110792.2(MECP2):c.1165_1234del; p.Lys389fs
HGVS:
  • NC_000023.11:g.154030635_154030704del
  • NG_007107.3:g.111405_111474del
  • NM_001110792.2:c.1165_1234delMANE SELECT
  • NM_001316337.2:c.850_919del
  • NM_001369391.2:c.850_919del
  • NM_001369392.2:c.850_919del
  • NM_001369393.2:c.850_919del
  • NM_001369394.2:c.850_919del
  • NM_001386137.1:c.460_529del
  • NM_001386138.1:c.460_529del
  • NM_001386139.1:c.460_529del
  • NM_004992.3:c.1129_1198del
  • NM_004992.4:c.1129_1198del
  • NP_001104262.1:p.Lys389fs
  • NP_001303266.1:p.Lys284fs
  • NP_001356320.1:p.Lys284fs
  • NP_001356321.1:p.Lys284fs
  • NP_001356322.1:p.Lys284fs
  • NP_001356323.1:p.Lys284fs
  • NP_001373066.1:p.Lys154fs
  • NP_001373067.1:p.Lys154fs
  • NP_001373068.1:p.Lys154fs
  • NP_004983.1:p.Lys377fs
  • LRG_764t1:c.1165_1234del
  • LRG_764t2:c.1129_1198del
  • LRG_764:g.111405_111474del
  • LRG_764p1:p.Lys389fs
  • LRG_764p2:p.Lys377fs
  • NC_000023.10:g.153296086_153296155del
  • NG_007107.2:g.111429_111498del
  • NM_004992.3:c.1129_1198del70
  • p.K377Pfsx9
Note:
70-nt deletion in exon 4 of gene MECP2.
Protein change:
K154fs
Links:
dbSNP: rs1557135353
NCBI 1000 Genomes Browser:
rs1557135353
Molecular consequence:
  • NM_001110792.2:c.1165_1234del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001316337.2:c.850_919del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001369391.2:c.850_919del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001369392.2:c.850_919del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001369393.2:c.850_919del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001369394.2:c.850_919del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001386137.1:c.460_529del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001386138.1:c.460_529del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001386139.1:c.460_529del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_004992.4:c.1129_1198del - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
2

Condition(s)

Name:
Rett syndrome (RTT)
Synonyms:
Autism, dementia, ataxia, and loss of purposeful hand use; Rett's disorder
Identifiers:
MONDO: MONDO:0010726; MedGen: C0035372; Orphanet: 3095; Orphanet: 778; OMIM: 312750

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000700176Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN)
criteria provided, single submitter

(Gerald et al. (Semin Pediatr Neurol. 2018))
Benignpaternal, unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002569942ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)
Uncertain significance
(Jul 21, 2022)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedunknownno1not providednot provided1not providedclinical testing
not providedpaternalyes1not providednot provided1not providedclinical testing

Citations

PubMed

Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results.

Gerald B, Ramsey K, Belnap N, Szelinger S, Siniard AL, Balak C, Russell M, Richholt R, De Both M, Claasen AM, Schrauwen I, Huentelman MJ, Craig DW, Rangasamy S, Narayanan V.

Semin Pediatr Neurol. 2018 Jul;26:28-32. doi: 10.1016/j.spen.2017.08.008. Epub 2017 Aug 16.

PubMed [citation]
PMID:
29961512

Details of each submission

From Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN), SCV000700176.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
2not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyes1not providednot provided1not providednot providednot provided
2unknownno1not providednot provided1not providednot providednot provided

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002569942.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Lys377ProfsTer9) variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.(Lys377ProfsTer9) variant has been reported in 1 individual with an epilepsy and neurodevelopmental disorder (PMID 29655203), and 1 individual with developmental delay and autism where it was inherited from a mother with a history of learning difficulties (ClinVar SCV000190972.2) (PS4_Supporting has not been applied as it is unclear whether these citations reflect two independent occurrences). The p.(Lys377ProfsTer9) variant has also been found in a patient with an alternate molecular basis of disease (PMID 29961512). This patient had early infantile epileptic encephalopathy, however did not meet the diagnostic criteria for either typical or atypical Rett. The p.(Lys377ProfsTer9) variant was found to be inherited from this patient's father, who was reported as having a history of seizures as a child and learning disability but was otherwise described as unaffected (BS2_Supporting). Furthermore, this patient was also found to be heterozygous for a de novo (biological parentage confirmed) GNAO1 missense variant that was deemed to be causative of this patient's clinical presentation (BP5). In summary, the c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PVS1, PM2_supporting, BP5, BS2_Supporting).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 5, 2023