NM_020866.3:c.1867C>T

Variant names:

• chr13-69719517-G-A
• rs1872945891
• NM_020866.3:c.1867C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020866.3(KLHL1):​c.1867C>T​(p.His623Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.1867C>T	p.His623Tyr	missense_variant	Exon 9 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1684C>T	p.His562Tyr	missense_variant	Exon 8 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1348C>T	p.His450Tyr	missense_variant	Exon 9 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1198C>T	p.His400Tyr	missense_variant	Exon 9 of 11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.1867C>T	p.His623Tyr	missense_variant	Exon 9 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1684C>T	p.His562Tyr	missense_variant	Exon 8 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1867C>T (p.H623Y) alteration is located in exon 9 (coding exon 9) of the KLHL1 gene. This alteration results from a C to T substitution at nucleotide position 1867, causing the histidine (H) at amino acid position 623 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.97	L;.
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.41		Gain of catalytic residue at E618 (P = 0.0078);.;
MVP		0.92
MPC		0.40
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.54
gMVP		0.25
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs1872945891; hg19: chr13-70293649; COSMIC: COSV106112697;