VCV000002436.38 - ClinVar

NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp)

Variation ID: 2436 Accession: VCV000002436.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q12 12: 39332405 (GRCh38) [ NCBI UCSC ] 12: 39726207 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001173464.2:c.2860C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001166935.1:p.Arg954Trp	missense
NM_001173463.2:c.2821C>T	NP_001166934.1:p.Arg941Trp	missense
NM_001173465.2:c.2752C>T	NP_001166936.1:p.Arg918Trp	missense
NM_017641.4:c.2821C>T	NP_060111.2:p.Arg941Trp	missense
NC_000012.12:g.39332405G>A
NC_000012.11:g.39726207G>A
NG_017067.1:g.115986C>T
	Q7Z4S6:p.Arg954Trp

... more HGVS ... less HGVS

Protein change

R954W, R941W, R918W

Other names

NM_001173464.2(KIF21A):c.2860C>T

Canonical SPDI

NC_000012.12:39332404:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA115554 UniProtKB: Q7Z4S6#VAR_019403 OMIM: 608283.0001 dbSNP: rs121912585 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KIF21A		-	-	GRCh38 GRCh37	264	285

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital fibrosis of extraocular muscles type 1	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000002538.21
Fibrosis of extraocular muscles, congenital, 3b	Pathogenic (1)	no assertion criteria provided	Jul 1, 2009	RCV000002539.5
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000267056.25
KIF21A-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 26, 2024	RCV003398420.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447791.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Congenital ptosis (present) Sex: female
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital fibrosis of extraocular muscles type 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581232.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4_MOD, PM5, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (May 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital fibrosis of extraocular muscles type 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893981.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026365.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PS4, PM1, PM2_SUP, PS3
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital fibrosis of extraocular muscles type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368022.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PS2_VSTR,PP1_VSTR,PS4,PS3_MOD,PM5,PM2_SUP,PP3 Clinical Features: Abnormal optic disc morphology (present) , Bilateral ptosis (present) , Moderate global developmental delay (present) , Abnormality of eye movement (present) Sex: male
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital fibrosis of extraocular muscles type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002766990.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 14595441‚ 24656932 Comment: 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 … (more) 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 (less)
Pathogenic (Jan 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329961.7 First in ClinVar: Dec 06, 2016 Last updated: Jan 21, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Dec 04, 2019)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Congenital fibrosis of extraocular muscles type 1 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001423777.2 First in ClinVar: Jul 27, 2020 Last updated: Mar 04, 2023	Publications: PubMed (2) PubMed: 14595441‚ 15621876 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Congenital fibrosis of extraocular muscles type 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV004800952.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024	Publications: PubMed (1) PubMed: 39033378 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a44d7809-f73f-4acc-99ea-e13335fa0468 Comment: 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 … (more) 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). (less)
Pathogenic (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital fibrosis of extraocular muscles type 1 Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV005045143.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Comment: The KIF21A c.2860C>T (p.Arg954Trp) variant has been reported in over 30 individuals affected with congenital fibrosis of extraocular muscles and is reported to segregate with … (more) The KIF21A c.2860C>T (p.Arg954Trp) variant has been reported in over 30 individuals affected with congenital fibrosis of extraocular muscles and is reported to segregate with disease in multiple families (Al-Haddad C et al., PMID: 33251926; Chen M et al., PMID: 36138147; Yamada K et al., PMID: 14595441). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. In vivo mouse models demonstrate that this variant results in a gain-of-function effect through attenuation of KIF21A autoinhibition (Cheng L et al., PMID: 24656932). Furthermore, computational predictors indicate that the variant is damaging, evidence that correlates with impact to KIF21A function. Two additional variants in the same codon, c.2861G>T (p.Arg954Leu) and c.2861G>C (p.Arg954Gln), have been reported in affected individuals and are considered pathogenic (Yamada K et al., PMID: 14595441; Yang X et al., PMID: 21042561; ClinVar Variation ID: 2437). This variant has been reported in the ClinVar database as a germline pathogenic variant by nine submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
Pathogenic (Jun 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001747054.20 First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jul 01, 2009)	no assertion criteria provided Method: literature only	FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022696.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 14595441‚ 15621876‚ 15621877‚ 15827546‚ 19551685 Comment on evidence: In patients with congenital fibrosis of extraocular muscles-1 (135700), Yamada et al. (2003) identified a C-to-T transition at nucleotide 2860 of the KIF21A gene, resulting … (more) In patients with congenital fibrosis of extraocular muscles-1 (135700), Yamada et al. (2003) identified a C-to-T transition at nucleotide 2860 of the KIF21A gene, resulting in an arg954-to-trp (R954W) substitution. R954W was the most frequent mutation in the KIF21A gene identified as the cause of FEOM1 by Yamada et al. (2003). Yamada et al. (2003) published a picture of a child with FEOM1 who harbored the R954W mutation and had bilateral ptosis and bilateral infraducted (downward) eye position in primary gaze with a chin-up head posture. She could not raise either eye above the neckline. Tiab et al. (2004) identified this mutation in 3 familial cases of CFEOM1 in patients of Swiss, Turkish, and French origin, respectively, and in a sporadic case in an Iranian patient. Ali et al. (2004) identified this mutation in affected members of a 4-generation Indian family with FEOM1. Ali et al. (2004) concluded that the high mutability of this CpG dinucleotide (see also 608283.0002) may result, in part, from its methylated state. Lin et al. (2005) identified a heterozygous R943W mutation in affected members of 2 Taiwanese families with classic CFEOM1 and an unrelated Taiwanese patient with sporadic CFEOM1. Affected members of a third Taiwanese family with a diagnosis of CFEOM3 (CFEOM3B; see 135700) were also found to carry the heterozygous mutation. The phenotype in the third family was considered different because of intrafamilial variation in disease severity. Two members had classic disease with severe ptosis and fixed eyes. Three other members were all affected, but these individuals could still move their eyes, and severity between the 2 eyes also differed. The molecular findings indicated that the CFEOM3 phenotype can be caused by KIF21A mutations, and that the expression of KIF21A mutations may be variable. In fact, Lin et al. (2005) even suggested that the third family may be better described as CFEOM1 with variability in expression. Rudolph et al. (2009) reported 3 families and 2 unrelated patients with CFEOM1 due to a heterozygous R943W mutation. All patients were of German origin, except 1 who was Turkish. The phenotype was relatively homogeneous: affected individuals showed bilateral restricted upgaze with compensatory chin elevation, ptosis, and variable limitations of horizontal gaze motility. Some had esotropia and/or exotropia. Many patients had corrective surgery of the extraocular muscles. In 1 family, affected individuals also had mental disability or mental retardation, which Rudolph et al. (2009) postulated may indicate that the syndrome can be associated with more general neurologic dysfunction in addition to impairment in ocular motility. Haplotype analysis did not indicate a founder effect. (less)
Pathogenic (Jul 01, 2009)	no assertion criteria provided Method: literature only	FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 3B Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022697.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 14595441‚ 15621876‚ 15621877‚ 15827546‚ 19551685 Comment on evidence: In patients with congenital fibrosis of extraocular muscles-1 (135700), Yamada et al. (2003) identified a C-to-T transition at nucleotide 2860 of the KIF21A gene, resulting … (more) In patients with congenital fibrosis of extraocular muscles-1 (135700), Yamada et al. (2003) identified a C-to-T transition at nucleotide 2860 of the KIF21A gene, resulting in an arg954-to-trp (R954W) substitution. R954W was the most frequent mutation in the KIF21A gene identified as the cause of FEOM1 by Yamada et al. (2003). Yamada et al. (2003) published a picture of a child with FEOM1 who harbored the R954W mutation and had bilateral ptosis and bilateral infraducted (downward) eye position in primary gaze with a chin-up head posture. She could not raise either eye above the neckline. Tiab et al. (2004) identified this mutation in 3 familial cases of CFEOM1 in patients of Swiss, Turkish, and French origin, respectively, and in a sporadic case in an Iranian patient. Ali et al. (2004) identified this mutation in affected members of a 4-generation Indian family with FEOM1. Ali et al. (2004) concluded that the high mutability of this CpG dinucleotide (see also 608283.0002) may result, in part, from its methylated state. Lin et al. (2005) identified a heterozygous R943W mutation in affected members of 2 Taiwanese families with classic CFEOM1 and an unrelated Taiwanese patient with sporadic CFEOM1. Affected members of a third Taiwanese family with a diagnosis of CFEOM3 (CFEOM3B; see 135700) were also found to carry the heterozygous mutation. The phenotype in the third family was considered different because of intrafamilial variation in disease severity. Two members had classic disease with severe ptosis and fixed eyes. Three other members were all affected, but these individuals could still move their eyes, and severity between the 2 eyes also differed. The molecular findings indicated that the CFEOM3 phenotype can be caused by KIF21A mutations, and that the expression of KIF21A mutations may be variable. In fact, Lin et al. (2005) even suggested that the third family may be better described as CFEOM1 with variability in expression. Rudolph et al. (2009) reported 3 families and 2 unrelated patients with CFEOM1 due to a heterozygous R943W mutation. All patients were of German origin, except 1 who was Turkish. The phenotype was relatively homogeneous: affected individuals showed bilateral restricted upgaze with compensatory chin elevation, ptosis, and variable limitations of horizontal gaze motility. Some had esotropia and/or exotropia. Many patients had corrective surgery of the extraocular muscles. In 1 family, affected individuals also had mental disability or mental retardation, which Rudolph et al. (2009) postulated may indicate that the syndrome can be associated with more general neurologic dysfunction in addition to impairment in ocular motility. Haplotype analysis did not indicate a founder effect. (less)
Pathogenic (Jan 26, 2024)	no assertion criteria provided Method: clinical testing	KIF21A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104605.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
click to load more click to collapse

Comment:

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

Comment:

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)

Comment:

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.

Comment:

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).

Comment:

The KIF21A c.2860C>T (p.Arg954Trp) variant has been reported in over 30 individuals affected with congenital fibrosis of extraocular muscles and is reported to segregate with disease in multiple families (Al-Haddad C et al., PMID: 33251926; Chen M et al., PMID: 36138147; Yamada K et al., PMID: 14595441). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. In vivo mouse models demonstrate that this variant results in a gain-of-function effect through attenuation of KIF21A autoinhibition (Cheng L et al., PMID: 24656932). Furthermore, computational predictors indicate that the variant is damaging, evidence that correlates with impact to KIF21A function. Two additional variants in the same codon, c.2861G>T (p.Arg954Leu) and c.2861G>C (p.Arg954Gln), have been reported in affected individuals and are considered pathogenic (Yamada K et al., PMID: 14595441; Yang X et al., PMID: 21042561; ClinVar Variation ID: 2437). This variant has been reported in the ClinVar database as a germline pathogenic variant by nine submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.	Jurgens JA	Genetics in medicine : official journal of the American College of Medical Genetics	2024	PMID: 39033378
Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.	Cheng L	Neuron	2014	PMID: 24656932
KIF21A variant R954W in familial or sporadic cases of CFEOM1.	Rudolph G	European journal of ophthalmology	2009	PMID: 19551685
KIF21A gene c.2860C>T mutation in congenital fibrosis of extraocular muscles type 1 and 3.	Lin LK	Molecular vision	2005	PMID: 15827546
Mutation analysis of the KIF21A gene in an Indian family with CFEOM1: implication of CpG methylation for most frequent mutations.	Ali M	Ophthalmic genetics	2004	PMID: 15621877
Mutation analysis of KIF21A in congenital fibrosis of the extraocular muscles (CFEOM) patients.	Tiab L	Ophthalmic genetics	2004	PMID: 15621876
Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).	Yamada K	Nature genetics	2003	PMID: 14595441
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a44d7809-f73f-4acc-99ea-e13335fa0468	-	-	-	-

Text-mined citations for rs121912585 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912585 ...