Genetic Variant KMT2D:p.Arg5179His (chr12-49026430-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_003482.4(KMT2D):c.15536G>A(p.Arg5179His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5179C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

KMT2D links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain FYR N-terminal (size 60) in uniprot entity KMT2D_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_003482.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-49026431-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

PP5

Variant 12-49026430-C-T is Pathogenic according to our data. Variant chr12-49026430-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49026430-C-T is described in Lovd as [Pathogenic]. Variant chr12-49026430-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.15536G>A	p.Arg5179His	missense_variant	Exon 49 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.15536G>A	p.Arg5179His	missense_variant	Exon 49 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kabuki syndrome 1

Pathogenic:5

Sep 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Kabuki syndrome 1 (MIM#147920) and branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (MIM#620186). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMIDs: 21882399, 31949313). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated FYRN family domain (DECIPHER). (I) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternate amino acid changes have been observed in unrelated individuals diagnosed with Kabuki syndrome: (p.Arg5179Cys), (p.Arg5179Leu), and (p.Arg5179Pro). Each variant has been reported in ClinVar as pathogenic or likely pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Clinical laboratories in ClinVar have reported this variant as pathogenic four times, and likely pathogenic once. This variant has been seen in multiple unrelated individuals diagnosed with Kabuki syndrome (PMIDs: 20711175, 37043208). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed)(by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 27, 2015

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 30, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 18, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 25755104, 20711175, 27302555, 28475860, 21671394, 28404210, 23913813, 30459467, 32368696, 28991257, 36891680, 37043208, 31941532, 37010288, 35904121) -

Kabuki syndrome

Pathogenic:1

Mar 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5179 of the KMT2D protein (p.Arg5179His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kabuki syndrome (PMID: 20711175, 23913813, 25755104, 27302555). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7536). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.094

MutationAssessor

Pathogenic

3.2

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.69

Sift

Uncertain

0.010

Polyphen

0.84

Vest4

0.94

MutPred

0.61

Loss of MoRF binding (P = 0.0215);

MVP

0.85

MPC

1.2

ClinPred

0.96

GERP RS

4.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.57

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over