VCV000235469.12 - ClinVar

NM_001303052.2(MYT1L):c.1706G>A (p.Arg569Gln)

Germline

Classification

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.

(7)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001303052.2(MYT1L):c.1706G>A (p.Arg569Gln)

Variation ID: 235469 Accession: VCV000235469.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p25.3 2: 1912023 (GRCh38) [ NCBI UCSC ] 2: 1915795 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jun 9, 2016	Jul 29, 2024	Oct 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001303052.2:c.1706G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001289981.1:p.Arg569Gln	missense
NM_001329844.2:c.1706G>A	NP_001316773.1:p.Arg569Gln	missense
NM_001329845.1:c.1706G>A	NP_001316774.1:p.Arg569Gln	missense
NM_001329846.3:c.1700G>A	NP_001316775.1:p.Arg567Gln	missense
NM_001329847.2:c.1700G>A	NP_001316776.1:p.Arg567Gln	missense
NM_001329848.1:c.1700G>A	NP_001316777.1:p.Arg567Gln	missense
NM_001329849.3:c.1700G>A	NP_001316778.1:p.Arg567Gln	missense
NM_001329851.3:c.1706G>A	NP_001316780.1:p.Arg569Gln	missense
NM_001329852.3:c.1700G>A	NP_001316781.1:p.Arg567Gln	missense
NM_015025.3:c.[1700G>A]
NM_015025.4:c.1700G>A	NP_055840.2:p.Arg567Gln	missense
NC_000002.12:g.1912023C>T
NC_000002.11:g.1915795C>T
NG_051313.1:g.424366G>A

... more HGVS ... less HGVS

Protein change

R567Q, R569Q

Other names

Canonical SPDI

NC_000002.12:1912022:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10581322 OMIM: 613084.0003 dbSNP: rs878853045 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
MYT1L		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	485	555

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 16, 2022	RCV000224698.5
Intellectual disability	Likely pathogenic (1)	criteria provided, single submitter	Apr 20, 2020	RCV001257695.2
Intellectual disability, autosomal dominant 39	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 26, 2018	RCV000754090.12

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.
Likely pathogenic (Apr 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001434506.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Clinical Features: Macrocephaly (present) , moderate to severe intellectual disability (present) , seizures (present) , normal MRI (present) , No language (present) , very reduced autonomy (present) Family history: no Age: 10-19 years Sex: male Tissue: blood Method: targeted capture
Likely pathogenic (Jan 22, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: de novo	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281074.1 First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016
Likely pathogenic (Feb 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 39 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001526483.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (1) PubMed: 28859103 Comment: This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in a … (more) This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in a patient with intellectual disability, plagiocephaly, 5th finger clinodactyly, an ataxic gait, hyperphagia, and cerebral atrophy [PMID 28859103, reported as p.Arg569Gln] (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 39 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073312.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Comment: The missense variant p.R567Q in MYT1L (NM_015025.4) has been previously reported as a de novo variant in an affected child (Blanchet P et al). The … (more) The missense variant p.R567Q in MYT1L (NM_015025.4) has been previously reported as a de novo variant in an affected child (Blanchet P et al). The variant has been submitted to ClinVar as Likely Pathogenic. The p.R567Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R567Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 567 of MYT1L is conserved in all mammalian species. The nucleotide c.1700 in MYT1L is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Global developmental delay (present) , Microcephaly (present) , Hyperintensity of cerebral white matter on MRI (present) , Atypical behavior (present)
Pathogenic (Oct 16, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002584188.2 First in ClinVar: Oct 22, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28859103, 28135719, 33004838, 32579932, 34748075) (less)
Pathogenic (May 13, 2021)	no assertion criteria provided Method: clinical testing	Intellectual disability, autosomal dominant 39 Affected status: yes Allele origin: de novo	Pediatric Genetics Clinic, Sheba Medical Center Accession: SCV001712201.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Clinical Features: Global developmental delay (present) , Seizure (present) Secondary finding: no
Pathogenic (Jul 19, 2024)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 39 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000882425.3 First in ClinVar: Jan 22, 2019 Last updated: Jul 29, 2024	Publications: PubMed (1) PubMed: 28859103 Comment on evidence: In a 9-year-old boy (patient 2; DECIPHER ID 279017) with autosomal dominant intellectual developmental disorder-39 and early-onset obesity (MRD39; 616521), Blanchet et al. (2017) identified … (more) In a 9-year-old boy (patient 2; DECIPHER ID 279017) with autosomal dominant intellectual developmental disorder-39 and early-onset obesity (MRD39; 616521), Blanchet et al. (2017) identified a de novo heterozygous transition (g.1915795C-T, GRCh37) in the MYT1L gene, resulting in an arg569-to-gln (R569Q) substitution. (less)

Comment:

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in a patient with intellectual disability, plagiocephaly, 5th finger clinodactyly, an ataxic gait, hyperphagia, and cerebral atrophy [PMID 28859103, reported as p.Arg569Gln]

Comment:

The missense variant p.R567Q in MYT1L (NM_015025.4) has been previously reported as a de novo variant in an affected child (Blanchet P et al). The variant has been submitted to ClinVar as Likely Pathogenic. The p.R567Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R567Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 567 of MYT1L is conserved in all mammalian species. The nucleotide c.1700 in MYT1L is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28859103, 28135719, 33004838, 32579932, 34748075)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.	Blanchet P	PLoS genetics	2017	PMID: 28859103

Text-mined citations for rs878853045 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001303052.2(MYT1L):c.1706G>A (p.Arg569Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs878853045 ...