rs121912585

chr12-39332405-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001173464.2(KIF21A):c.2860C>T(p.Arg954Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,534 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R954Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KIF21A NM_001173464.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.58

Genes affected

KIF21A (HGNC:19349): (kinesin family member 21A) This gene encodes a member of the KIF4 subfamily of kinesin-like motor proteins. The encoded protein is characterized by an N-terminal motor domain a coiled-coil stalk domain and a C-terminal WD-40 repeat domain. This protein may be involved in microtubule dependent transport. Mutations in this gene are the cause of congenital fibrosis of extraocular muscles-1. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a coiled_coil_region (size 88) in uniprot entity KI21A_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_001173464.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-39332404-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KIF21A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• PP5: Variant 12-39332405-G-A is Pathogenic according to our data. Variant chr12-39332405-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-39332405-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF21A	NM_001173464.2	c.2860C>T	p.Arg954Trp	missense_variant	21/38	ENST00000361418.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF21A	ENST00000361418.10	c.2860C>T	p.Arg954Trp	missense_variant	21/38	1	NM_001173464.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with fibrosis of extraocular muscles, congenital, 1 (MIM#135700) and fibrosis of extraocular muscles, congenital, 3B (MIM#135700). Mouse models have ruled out loss of function and dominant negative, and suggest that gain of function may occur through the attenuation of KIF21A autoinhibition (PMID: 24656932). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the third coiled-coil motif (DECIPHER, PMID: 14595441). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg954Gln) has been classified as pathogenic by a clinical laboratory in ClinVar, and observed in several individuals with congenital fibrosis of extraocular muscles in the literature (PMID: 14595441). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in many individuals with congenital fibrosis of extraocular muscles in the literature (PMID: 14595441). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 04, 2019	The KIF21A c.2860C>T (p.Arg954Trp) missense variant has been reported in at least two studies in which it was identified in a heterozygous state in 36 out of 49 unrelated individuals affected with congenital fibrosis of the extraocular muscles (CFEOM), including both familial and sporadic cases. In eleven of these individuals, the variant was found in a de novo state (Yamada et al. 2003; Tiab et al. 2004). The variant showed co-segregation with disease in at least fifteen families (Yamada et al. 2003; Tiab et al. 2004). The p.Arg954Trp variant was absent from 410 control alleles from individuals from different ethnicities and is not found in the Genome Aggregation Database in a region of good coverage so is presumed to be rare. Based on the absence from public frequency databases, occurrence de novo, and application of ACMG criteria, the p.Arg954Trp variant is classified as pathogenic for congenital fibrosis of the extraocular muscles. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 12, 2024	The heterozygous p.Arg954Trp variant in KIF21A (also known as p.Arg941Trp due to a difference in cDNA numbering) was identified by our study in 4 family members with congenital fibrosis of the extraocular muscles, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg954Trp variant in KIF21A has been previously reported in over 30 unrelated individuals with congenital fibrosis of the extraocular muscles (PMID: 14595441) and segregated with disease in over 133 affected relatives from 21 families (PMID: 14595441). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has been reported de novo in over 8 individuals with confirmed paternity and maternity (PMID: 14595441). This variant has also been reported in ClinVar (Variation ID: 2436) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. Multiple variants in the same region as the p.Arg954Trp variant have been reported in association with disease in the literature and in ClinVar and the p.Arg954Trp variant is located in a region of KIF21A that is essential to kinesin dimerization, suggesting that this variant is in a hotspot and functional domain and slightly supports pathogenicity (PMID: 14595441, ClinVar Variation ID: 2440, 2441, 2442). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg954Gln, has been reported in in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 14595441, Variation ID: 2437). Animal models in mice have shown that this variant causes congenital fibrosis of the extraocular muscles (PMID: 24656932). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital fibrosis of the extraocular muscles type 1. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3, PS4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP1_Strong, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 20, 2022	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	Published functional studies demonstrate a damaging effect that results in a gain-of-function effect, with knock-in mice exhibiting a congenital fibrosis of the extraocular muscles type 1 phenotype (Kakinuma et al., 2009; Chen et al., 2014); Not observed in large population cohorts (gnomAD); Also reported as R954W using alternate nomenclature; This variant is associated with the following publications: (PMID: 18363169, 19559006, 26190014, 23799907, 21042561, 24426772, 24656932, 23336411, 27513105, 28930843, 30555664, 14595441, 32901917, 33251926) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jul 07, 2023	PS4, PM1, PM2_SUP, PS3 -

KIF21A-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

The KIF21A c.2860C>T variant is predicted to result in the amino acid substitution p.Arg954Trp. This variant is the most commonly reported variant in individuals with autosomal dominant congenital fibrosis of the extraocular muscles (Yamada et al. 2003. PubMed ID: 14595441; Rudolph et al. 2009. PubMed ID: 19551685; Yang et al. 2010. PubMed ID: 21042561). This variant has not been documented in a large population database, indicating it is rare. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/2436). Given all the evidence, we interpret c.2860C>T (p.Arg954Trp) as pathogenic. -

Fibrosis of extraocular muscles, congenital, 3b Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.;T;.;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
Polyphen		1.0, 1.0	.;D;.;.;D;.
Vest4		0.91, 0.89, 0.87
MutPred		0.38		.;.;.;.;Loss of ubiquitination at K952 (P = 0.0272);.;
MVP		0.94
MPC		0.94
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.92
gMVP		0.67

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: rs121912585; hg19: chr12-39726207; COSMIC: COSV100735326; COSMIC: COSV100735326;