3-183650357-A-G

Position:

• chr3-183650357-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017644.3(KLHL24):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL24 NM_017644.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.70

Genes affected

KLHL24 (HGNC:25947): (kelch like family member 24) The protein encoded by this gene is a ubiquitin ligase substrate receptor and is regulated by autoubiquitination. Variations in the translation initiation codon of this gene have been found, which result in an N-terminally truncated but more stable protein due to loss of the autoubiquitination function. The more stable mutant protein causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and the potentially life-threatening disease epidermolysis bullosa. The encoded protein is also involved in the regulation of kainate receptors. [provided by RefSeq, Mar 2017]

KLHL24 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-183650357-A-G is Pathogenic according to our data. Variant chr3-183650357-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 264648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-183650357-A-G is described in Lovd as [Pathogenic]. Variant chr3-183650357-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL24	NM_017644.3	c.1A>G	p.Met1?	start_lost	3/8	ENST00000242810.11	NP_060114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL24	ENST00000242810.11	c.1A>G	p.Met1?	start_lost	3/8	1	NM_017644.3	ENSP00000242810.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 27, 2018	PS3, PM2, PM6, PP3, PP4, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 15, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 very strong, PP1 supporting -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	Follow-up reports have identified evidence of cardiac involvement such as increased blood levels of a biomarker for heart disease, significant cardiac dysfunction by imaging, or adult-onset dilated cardiomyopathy (DCM) in a high proportion of these patients, and neurological involvement in a smaller proportion (Schwieger-Briel et al., 2018; Yenamandra et al., 2018); The c.1 A>G variant alters the initiator Methionine codon, and the resultant protein is described as p.Met1? using a question mark to signify that it is not certain if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; however, published functional studies demonstrate that a downstream in-frame Met initiation codon was used to initiate translation of a protein missing the initial 28 amino acids of the KLHL24 protein (denoted p.Val2_Met29del or KLHL24delta28) in some patients (Lin et al., 2016; He et al., 2016); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27798626, 27889062, 28111128, 30120936, 29779254, 34292882, 34008892, 32484238) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This sequence change affects the initiator methionine of the KLHL24 mRNA. The next in-frame methionine is located at codon 29. Loss-of-function variants in KLHL24 are expected to cause autosomal recessive hypertrophic cardiomyopathy (PMID: 30715372). However, initiator codon variants and truncations that occur before p.Met29 are unlikely to result in loss of function (PMID: 35975634). This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with autosomal dominant epidermolysis bullosa (PMID: 27889062). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264648). For these reasons, this variant has been classified as Pathogenic. -

KLHL24-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The KLHL24 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported as a recurrent de novo variant in individuals with epidermolysis bullosa (see for example, He et al. 2016. PubMed ID: 27889062; Lee et a 2017. PubMed ID: 28111128; Table S1, Chen et al. 2020. PubMed ID: 32484238). Alternate nucleotide changes predicted to result in start-loss (1A>T, 2T>C, 2T>G, 3G>T, c.3G>A; p.Met1?), have also been reported in individuals with epidermolysis bullosa (Lin et al. 2016. PubMed ID: 27798626; He et al. 2016. PubMed ID: 27889062; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Epidermolysis bullosa simplex, Koebner type Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;research

Clinical Genetics Laboratory of Dermatology, Peking University First Hospital

Sep 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;T;.;T;T;T;.;.;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.097	D
PROVEAN	Benign	-0.50	N;N;D;N;D;N;N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.32	B;.;.;.;.;.;.;.;B;.;B
Vest4		0.85
MutPred		0.92		Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);
MVP		0.90
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
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

Other links and lift over

dbSNP: rs886037956; hg19: chr3-183368145; COSMIC: COSV99665232;