NM_003482.4(KMT2D):c.5993A>G (p.Tyr1998Cys) AND Kabuki syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 22, 2023
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:: RCV003588758.2

Allele description [Variation Report for NM_003482.4(KMT2D):c.5993A>G (p.Tyr1998Cys)]

NM_003482.4(KMT2D):c.5993A>G (p.Tyr1998Cys)

Gene:

KMT2D:lysine methyltransferase 2D [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.12

Genomic location:

Preferred name:

NM_003482.4(KMT2D):c.5993A>G (p.Tyr1998Cys)

HGVS:

NC_000012.12:g.49042205T>C
NG_027827.1:g.18120A>G
NM_003482.4:c.5993A>GMANE SELECT
NP_003473.3:p.Tyr1998Cys
NC_000012.11:g.49435988T>C
NM_003482.3:c.5993A>G

Protein change:

Y1998C

Links:

dbSNP: rs1292951816

NCBI 1000 Genomes Browser:

rs1292951816

Molecular consequence:

NM_003482.4:c.5993A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Kabuki syndrome
Synonyms:: Kabuki make-up syndrome; Niikawa-Kuroki syndrome
Identifiers:: MONDO: MONDO:0016512; MedGen: C0796004; OMIM: PS147920

Recent activity

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Homo sapiens hypothetical protein BC000993 (LOC130026), mRNA
Homo sapiens hypothetical protein BC000993 (LOC130026), mRNA
gi|19924000|ref|NM_138468.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004295040	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25142838, 30459467, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004295040

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 22, 2023)

germline

clinical testing

PubMed (3)
[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	clinical testing

Citations

PubMed

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome.

Lin JL, Lee WI, Huang JL, Chen PK, Chan KC, Lo LJ, You YJ, Shih YF, Tseng TY, Wu MC.

Clin Genet. 2015 Sep;88(3):255-60. doi: 10.1111/cge.12484. Epub 2014 Oct 14.

PubMed [citation]

PMID:: 25142838

A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population.

Faundes V, Malone G, Newman WG, Banka S.

J Hum Genet. 2019 Feb;64(2):161-170. doi: 10.1038/s10038-018-0536-6. Epub 2018 Nov 20.

PubMed [citation]

PMID:: 30459467

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295040.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1998 of the KMT2D protein (p.Tyr1998Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kabuki syndrome (PMID: 25142838, 30459467). ClinVar contains an entry for this variant (Variation ID: 1303257). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KMT2D protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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