ClinVar Genomic variation as it relates to human health
NM_001080510.5(METTL23):c.169_172del (p.His57fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001080510.5(METTL23):c.169_172del (p.His57fs)
Variation ID: 144023 Accession: VCV000144023.19
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17q25.1 17: 76733060-76733063 (GRCh38) [ NCBI UCSC ] 17: 74729142-74729145 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 25, 2014 Mar 5, 2024 Apr 21, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- H53fs, H57fs
- Other names
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- Canonical SPDI
- NC_000017.11:76733059:CTCACT:CT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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METTL23 | - | - |
GRCh38 GRCh37 |
49 | 65 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2022 | RCV000133532.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2015 | RCV000622976.3 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 21, 2023 | RCV000598829.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 44
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001426514.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
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Likely pathogenic
(Jun 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067338.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the METTL23 gene demonstrated a 4 base pair deletion in exon 3, c.169_172del. This sequence change results in an amino acid … (more)
DNA sequence analysis of the METTL23 gene demonstrated a 4 base pair deletion in exon 3, c.169_172del. This sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the mutation, p.His57Valfs*11 (NM_001080510.3). This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated METTL23 protein with potentially abnormal function. The METTL23 gene has 10 different transcripts and this sequence change is present in 6 of the 10 transcripts. In the remaining 4 transcripts, the variant falls within a non-coding region. This sequence change was identified in the homozygous state in multiple individuals with intellectual disability and dysmorphic features in a large, consanguineous family of Yemeni origin (PMID: 24501276). The c.169_172del sequence change has been described in the gnomAD database with a population frequency of 0.0097% (dbSNP rs1175461719); however, it has not been observed in the homozygous state in any individuals. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 44
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766723.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Mar 09, 2015)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740840.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Neurodevelopmental delay (present) , Intellectual disability, mild (present) , Failure to thrive (present) , Muscular hypotonia (present) , Eczema (present) , Tibial torsion (present) , … (more)
Neurodevelopmental delay (present) , Intellectual disability, mild (present) , Failure to thrive (present) , Muscular hypotonia (present) , Eczema (present) , Tibial torsion (present) , Abnormality of the metatarsal bones (present) , Frontal bossing (present) , Prominent forehead (present) , Synophrys (present) , Wide nasal bridge (present) , Depressed nasal bridge (present) , Dysarthria (present) , Cafe-au-lait spot (present) , Lower limb muscle weakness (present) , Short stature (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Hypopituitarism (present) , Poor appetite (present) , Amblyopia (present) , Chronic otitis media (present) , Mitral valve prolapse (present) , Esotropia (present) , Growth hormone … (more)
Hypopituitarism (present) , Poor appetite (present) , Amblyopia (present) , Chronic otitis media (present) , Mitral valve prolapse (present) , Esotropia (present) , Growth hormone deficiency (present) , Broad forehead (present) , Hypothyroidism (present) , Posteriorly rotated ears (present) , Scoliosis (present) , Short stature (present) , Intellectual disability (present) , Narrow forehead (present) , Global developmental delay (present) (less)
Sex: male
Ethnicity/Population group: Caucasian/French/Italian
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Pathogenic
(Apr 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000709996.5
First in ClinVar: Apr 02, 2018 Last updated: Jun 10, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27870114, 32552793, 32860008, 24501276, 24626631) (less)
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Pathogenic
(Nov 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 44
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024342.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 44
Affected status: yes
Allele origin:
inherited
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Molecular Genetics Lab, CHRU Brest
Accession: SCV004697659.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
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Pathogenic
(Jul 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 44
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001761083.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
Clinical Features:
Intellectual disability (present) , Autism (present)
Secondary finding: no
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Pathogenic
(Jul 01, 2014)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 44
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000188607.2
First in ClinVar: Aug 25, 2014 Last updated: Apr 11, 2022 |
Comment on evidence:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability. | Bernkopf M | Human molecular genetics | 2014 | PMID: 24626631 |
METTL23, a transcriptional partner of GABPA, is essential for human cognition. | Reiff RE | Human molecular genetics | 2014 | PMID: 24501276 |
Text-mined citations for rs587777644 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.