VCV000431895.9 - ClinVar

NM_001197104.2(KMT2A):c.3460C>T (p.Arg1154Trp)

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_001197104.2(KMT2A):c.3460C>T (p.Arg1154Trp)

Variation ID: 431895 Accession: VCV000431895.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 118478092 (GRCh38) [ NCBI UCSC ] 11: 118348807 (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	Aug 20, 2017	May 26, 2024	Jan 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001197104.2:c.3460C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001184033.1:p.Arg1154Trp	missense
NM_005933.4:c.3460C>T	NP_005924.2:p.Arg1154Trp	missense
NC_000011.10:g.118478092C>T
NC_000011.9:g.118348807C>T
NG_027813.1:g.46603C>T
LRG_613:g.46603C>T
LRG_613t1:c.3460C>T	LRG_613p1:p.Arg1154Trp

... more HGVS ... less HGVS

Protein change

R1154W

Other names

Canonical SPDI

NC_000011.10:118478091: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: CA382824774 dbSNP: rs1555038090 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.
KMT2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2637	2849

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 (3)	criteria provided, multiple submitters, no conflicts	Jan 2, 2024	RCV000498743.5
Wiedemann-Steiner syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 10, 2023	RCV001007914.5

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.
Pathogenic (Jan 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wiedemann-Steiner syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV001167623.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Sex: female Secondary finding: no
Pathogenic (Dec 30, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589459.4 First in ClinVar: Aug 20, 2017 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: 30014449, 29203834, 29574747, 31044088, 30315573, 33043602, 33783954, 34469078) (less)
Likely pathogenic (Jul 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wiedemann-Steiner syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806871.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM6 moderated, PP1 supporting, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Fetal growth restriction (present) , Delayed ability to walk (present) , Trigonocephaly (present) , Primary microcephaly (present) , Microcephaly (present) , Decreased body weight (present) … (more) Fetal growth restriction (present) , Delayed ability to walk (present) , Trigonocephaly (present) , Primary microcephaly (present) , Microcephaly (present) , Decreased body weight (present) , Delayed fine motor development (present) , Small for gestational age (present) , Short stature (present) , Global developmental delay (present) , Abnormality of the frontal hairline (present) , Delayed ability to stand (present) , Diminished ability to concentrate (present) , Intellectual disability (present) , Delayed gross motor development (present) , Mild global developmental delay (present) , Focal-onset seizure (present) , Atypical behavior (present) , Intellectual disability, mild (present) , Delayed speech and language development (present) , Agitation (present) , Hyperpigmentation of the skin (present) , Depigmentation/hyperpigmentation of skin (present) , Mild intrauterine growth retardation (present) , Restlessness (present) , Delayed ability to sit (present) , Short attention span (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Likely pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wiedemann-Steiner syndrome Affected status: yes Allele origin: de novo	Daryl Scott Lab, Baylor College of Medicine Accession: SCV004102703.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004540601.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 29574747‚ 33043602‚ 29203834 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1154 of the KMT2A protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1154 of the KMT2A protein (p.Arg1154Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wiedemann-Steiner syndrome (PMID: 29574747, 33043602). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431895). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KMT2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KMT2A function (PMID: 29203834). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Apr 26, 2018)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031329.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)
Pathogenic (Feb 01, 2024)	no assertion criteria provided Method: clinical testing	Wiedemann-Steiner syndrome Affected status: yes Allele origin: de novo	Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital Accession: SCV005045322.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Number of individuals with the variant: 1 Ethnicity/Population group: Asia Geographic origin: China

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: 30014449, 29203834, 29574747, 31044088, 30315573, 33043602, 33783954, 34469078)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1154 of the KMT2A protein (p.Arg1154Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wiedemann-Steiner syndrome (PMID: 29574747, 33043602). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431895). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KMT2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KMT2A function (PMID: 29203834). For these reasons, this variant has been classified as Pathogenic.

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
Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.	Giangiobbe S	American journal of medical genetics. Part A	2020	PMID: 33043602
Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.	Baer S	Clinical genetics	2018	PMID: 29574747
Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome.	Lebrun N	European journal of human genetics : EJHG	2018	PMID: 29203834

Text-mined citations for rs1555038090 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001197104.2(KMT2A):c.3460C>T (p.Arg1154Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555038090 ...