rs1057518697

Positions:

• chrX-53210820-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004187.5(KDM5C):​c.1439C>T​(p.Pro480Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,861 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P480P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

Genes affected

KDM5C (HGNC:11114): (lysine demethylase 5C) This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain JmjC (size 166) in uniprot entity KDM5C_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_004187.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KDM5C. . Gene score misZ 5.1452 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant X-53210820-G-A is Pathogenic according to our data. Variant chrX-53210820-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 374324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.1439C>T	p.Pro480Leu	missense_variant	11/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.1439C>T	p.Pro480Leu	missense_variant	11/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097861 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363223

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: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Claes-Jensen type Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2022	Variant summary: KDM5C c.1439C>T (p.Pro480Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183427 control chromosomes. c.1439C>T has been reported in the literature in individuals affected with Mental Retardation, Syndromic, Claes-Jensen Type, X-Linked. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that p.P480L leads to reduced stability and enzymatic activity (Brookes_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	May 10, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Jun 19, 2014	A likely pathogenic variant in KDM5C was reported in this individual, who has delayed motor milestones, delayed speech, intellectual disability, hypotonia, dysmorphic features (prominent chin, mild plagiocephaly), short stature, microcephaly, strabismus, and an ectopic posterior pituitary. This change has been recently in two brothers affected with X-linked intellectual disability [PMID: 23356856]. A pathogenic variant in GLI2 (NM_005270.4; c.891delG) was also reported in this individual by our laboratory. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2021	Published functional studies demonstrate a damaging effect, including reduced protein stability and demethylase activity (Brookes et al., 2015); Not observed 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: 23356856, 27959697, 25666757, 29456765, 25666439) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	KDM5C: PS2, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2018

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense disrupts KDM5C protein function (PMID: 25666439). This variant has been observed to be de novo in both males and females affected with syndromic intellectual disability (PMID: 25666757, 27959697). It has also been observed to segregate with disease in related individuals (PMID: 23356856). ClinVar contains an entry for this variant (Variation ID: 374324). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 480 of the KDM5C protein (p.Pro480Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.0	.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.83
MutPred		0.82		.;Gain of helix (P = 0.1736);.;Gain of helix (P = 0.1736);.;
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1057518697; hg19: chrX-53240002; COSMIC: COSV64762787; COSMIC: COSV64762787;