NM_001197104.2(KMT2A):c.3460C>T (p.Arg1154Trp) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 2, 2024
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:: RCV000498743.4

Allele description [Variation Report for NM_001197104.2(KMT2A):c.3460C>T (p.Arg1154Trp)]

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

Gene:

KMT2A:lysine methyltransferase 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.118478092C>T
NG_027813.1:g.46603C>T
NM_001197104.2:c.3460C>TMANE SELECT
NM_005933.4:c.3460C>T
NP_001184033.1:p.Arg1154Trp
NP_001184033.1:p.Arg1154Trp
NP_005924.2:p.Arg1154Trp
LRG_613t1:c.3460C>T
LRG_613:g.46603C>T
LRG_613p1:p.Arg1154Trp
NC_000011.9:g.118348807C>T
NM_001197104.1:c.3460C>T
NM_005933.3:c.3460C>T

Protein change:

R1154W

Links:

dbSNP: rs1555038090

NCBI 1000 Genomes Browser:

rs1555038090

Molecular consequence:

NM_001197104.2:c.3460C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005933.4:c.3460C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000589459	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 30, 2021)	germline	clinical testing	Citation Link,
SCV004031329	Molecular Genetics laboratory, Necker Hospital	no assertion criteria provided	Likely pathogenic (Apr 26, 2018)	de novo	clinical testing
SCV004540601	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29574747, 33043602, 29203834, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000589459

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 30, 2021)

germline

clinical testing

Citation Link,

SCV004031329

Molecular Genetics laboratory, Necker Hospital

no assertion criteria provided

Likely pathogenic
(Apr 26, 2018)

de novo

clinical testing

SCV004540601

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 2, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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	de novo	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

Citations

PubMed

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Baer S, Afenjar A, Smol T, Piton A, Gérard B, Alembik Y, Bienvenu T, Boursier G, Boute O, Colson C, Cordier MP, Cormier-Daire V, Delobel B, Doco-Fenzy M, Duban-Bedu B, Fradin M, Geneviève D, Goldenberg A, Grelet M, Haye D, Heron D, Isidor B, et al.

Clin Genet. 2018 Jul;94(1):141-152. doi: 10.1111/cge.13254. Epub 2018 May 17. Review.

PubMed [citation]

PMID:: 29574747

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Giangiobbe S, Caraffi SG, Ivanovski I, Maini I, Pollazzon M, Rosato S, Trimarchi G, Lauriello A, Marinelli M, Nicoli D, Baldo C, Laurie S, Flores-Daboub J, Provenzano A, Andreucci E, Peluso F, Rizzo R, Stewart H, Lachlan K, Bayat A, Napoli M, Carboni G, et al.

Am J Med Genet A. 2020 Dec;182(12):2877-2886. doi: 10.1002/ajmg.a.61859. Epub 2020 Oct 11.

PubMed [citation]

PMID:: 33043602

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000589459.4

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

Description

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)

#	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 Molecular Genetics laboratory, Necker Hospital, SCV004031329.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004540601.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	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

Last Updated: May 26, 2024

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