NM_170606.3(KMT2C):c.4441C>T (p.Arg1481Ter) AND Kleefstra syndrome 2

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 16, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000074464.5

Allele description [Variation Report for NM_170606.3(KMT2C):c.4441C>T (p.Arg1481Ter)]

NM_170606.3(KMT2C):c.4441C>T (p.Arg1481Ter)

Gene:

KMT2C:lysine methyltransferase 2C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_170606.3(KMT2C):c.4441C>T (p.Arg1481Ter)

Other names:

NM_170606.2:c.4441C>T(p.Arg1481Ter)

HGVS:

NC_000007.14:g.152194506G>A
NG_033948.1:g.246500C>T
NM_170606.3:c.4441C>TMANE SELECT
NP_733751.2:p.Arg1481Ter
NC_000007.13:g.151891591G>A
NM_170606.2:c.4441C>T

Protein change:

R1481*; ARG1481TER

Links:

OMIM: 606833.0001; dbSNP: rs587777073

NCBI 1000 Genomes Browser:

rs587777073

Molecular consequence:

NM_170606.3:c.4441C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Kleefstra syndrome 2 (KLEFS2)
Identifiers:: MONDO: MONDO:0054701; MedGen: C4540395; OMIM: 617768

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000108480	OMIM	no assertion criteria provided	Pathogenic (Jul 13, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000787474	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 16, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 22726846, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000108480

OMIM

no assertion criteria provided

Pathogenic
(Jul 13, 2012)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000787474

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 16, 2018)

germline

curation

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability.

Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE, Wissink-Lindhout W, Fenckova M, van den Akker WM, Kasri NN, Nillesen WM, Prescott T, Clark RD, Devriendt K, van Reeuwijk J, de Brouwer AP, Gilissen C, Zhou H, Brunner HG, Veltman JA, Schenck A, van Bokhoven H.

Am J Hum Genet. 2012 Jul 13;91(1):73-82. doi: 10.1016/j.ajhg.2012.05.003. Epub 2012 Jun 21.

PubMed [citation]

PMID:: 22726846
PMCID:: PMC3397275

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000108480.4

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

Description

In a girl with Kleefstra syndrome-2 (KLEFS2; 617768), Kleefstra et al. (2012) identified a heterozygous C-to-T transition at nucleotide 4441 of the MLL3 gene that resulted in an arg1481-to-ter substitution (R1481X). The father was not available for testing, but neither the patient's mother nor either of her unaffected sisters (who carried the same paternal haplotype as the patient at the MLL3 locus) carried this mutation.

#	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 SIB Swiss Institute of Bioinformatics, SCV000787474.1

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

Description

This variant is interpreted as a Likely Pathogenic, for Kleefstra syndrome 2, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Moderate => PVS1 downgraded in strength to Moderate. PM6 => Assumed de novo, but without confirmation of paternity and maternity.

#	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: Oct 8, 2024

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