NM_001080510.5(METTL23):c.169_172del (p.His57fs) AND Intellectual disability, autosomal recessive 44

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Feb 2, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000133532.12

Allele description [Variation Report for NM_001080510.5(METTL23):c.169_172del (p.His57fs)]

NM_001080510.5(METTL23):c.169_172del (p.His57fs)

Gene:

METTL23:methyltransferase 23, arginine [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

NM_001080510.5(METTL23):c.169_172del (p.His57fs)

HGVS:

NC_000017.11:g.76733062_76733065del
NG_032905.1:g.9349_9352del
NG_041790.1:g.11233_11236del
NM_001080510.5:c.169_172delMANE SELECT
NM_001206983.3:c.169_172del
NM_001206984.3:c.169_172del
NM_001206985.3:c.-33_-30del
NM_001206986.3:c.-33_-30del
NM_001206987.3:c.-33_-30del
NM_001302703.2:c.169_172del
NM_001302704.2:c.-33_-30del
NM_001302705.2:c.157_160del
NM_001378348.1:c.169_172del
NM_001378349.1:c.169_172del
NM_001378350.1:c.157_160del
NM_001378351.1:c.157_160del
NM_001378352.1:c.157_160del
NM_001378353.1:c.157_160del
NM_001378354.1:c.-33_-30del
NP_001073979.3:p.His57fs
NP_001193912.1:p.His57fs
NP_001193912.1:p.His57fs
NP_001193913.1:p.His57fs
NP_001289632.1:p.His57fs
NP_001289634.1:p.His53fs
NP_001365277.1:p.His57fs
NP_001365278.1:p.His57fs
NP_001365279.1:p.His53fs
NP_001365280.1:p.His53fs
NP_001365281.1:p.His53fs
NP_001365282.1:p.His53fs
LRG_640:g.9349_9352del
NC_000017.10:g.74729144_74729147del
NM_001080510.3:c.169_172del
NM_001080510.4:c.169_172del
NM_001080510.4:c.169_172delCACT
NM_001206983.1:c.169_172delCACT
NM_001206983.2:c.169_172del

Protein change:

H53fs

Links:

OMIM: 615262.0001; dbSNP: rs587777644

NCBI 1000 Genomes Browser:

rs587777644

Molecular consequence:

NM_001206985.3:c.-33_-30del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001206986.3:c.-33_-30del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001206987.3:c.-33_-30del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001302704.2:c.-33_-30del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001378354.1:c.-33_-30del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001080510.5:c.169_172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001206983.3:c.169_172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001206984.3:c.169_172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001302703.2:c.169_172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001302705.2:c.157_160del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378348.1:c.169_172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378349.1:c.169_172del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378350.1:c.157_160del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378351.1:c.157_160del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378352.1:c.157_160del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378353.1:c.157_160del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Intellectual disability, autosomal recessive 44 (MRT44)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 44
Identifiers:: MONDO: MONDO:0014409; MedGen: C4014745; Orphanet: 88616; OMIM: 615942

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188607	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001426514	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV001761083	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Jul 3, 2020)	inherited	clinical testing	Citation Link,
SCV002024342	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766723	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24501276, 24626631, 25741868
SCV004697659	Molecular Genetics Lab, CHRU Brest	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32860008
PMCID:: PMC7852664

METTL23, a transcriptional partner of GABPA, is essential for human cognition.

Reiff RE, Ali BR, Baron B, Yu TW, Ben-Salem S, Coulter ME, Schubert CR, Hill RS, Akawi NA, Al-Younes B, Kaya N, Evrony GD, Al-Saffar M, Felie JM, Partlow JN, Sunu CM, Schembri-Wismayer P, Alkuraya FS, Meyer BF, Walsh CA, Al-Gazali L, Mochida GH.

Hum Mol Genet. 2014 Jul 1;23(13):3456-66. doi: 10.1093/hmg/ddu054. Epub 2014 Feb 5.

PubMed [citation]

PMID:: 24501276
PMCID:: PMC4049305

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000188607.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 7 affected members of a consanguineous Yemeni kindred with autosomal recessive intellectual developmental disorder-44 (MRT44; 615942), Reiff et al. (2014) identified a homozygous 4-bp deletion (c.169_172delCACT), in the METTL23 gene, resulting in a frameshift and premature termination (His57ValfsTer11). The mutation, which was found by homozygosity mapping and exome sequencing of the candidate region, was confirmed by Sanger sequencing and segregated with the disorder in the family. The variant was found at a low frequency (1 in 11,615) in the Exome Variant Server database, and a nearby 2-bp deletion (c.171_172delCT) was also present at a low frequency (2 in 11,622). The 4-bp deletion was not present in the 1000 Genomes Project database, in over 800 in-house exomes, or in 357 Saudi exomes. The identified mutation falls within a coding region of the highly conserved isoform 1 of METTL23, and in the 5-prime untranslated region of isoform 2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV001426514.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV001761083.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024342.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766723.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with METTL23-related intellectual disability (MIM#615942). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (26 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants have been classified as pathogenic, and observed in individuals with METTL23-related intellectual disability (ClinVar, LOVD, PMID: 24626631). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in a family with intellectual disability (ClinVar, PMID: 24501276). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has segregated in seven homozygous individuals within a single family (PMID: 24501276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics Lab, CHRU Brest, SCV004697659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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