This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
ClinVar Genomic variation as it relates to human health
NM_007317.3(KIF22):c.443C>T (p.Pro148Leu)
Germline
Classification
Help
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.
(10)
Help
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/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007317.3(KIF22):c.443C>T (p.Pro148Leu)
Variation ID: 30334 Accession: VCV000030334.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p11.2 16: 29798641 (GRCh38) [ NCBI UCSC ] 16: 29809962 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 29, 2024 May 13, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007317.3:c.443C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_015556.1:p.Pro148Leu missense NM_001256269.2:c.239C>T NP_001243198.1:p.Pro80Leu missense NM_001256270.1:c.239C>T NP_001243199.1:p.Pro80Leu missense NC_000016.10:g.29798641C>T NC_000016.9:g.29809962C>T NG_032055.1:g.12929C>T Q14807:p.Pro148Leu - Protein change
- P148L, P80L
- Other names
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- Canonical SPDI
- NC_000016.10:29798640:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| KIF22 | - | - |
GRCh38 GRCh37 |
326 | 611 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Oct 6, 2021 | RCV000023269.11 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 13, 2024 | RCV000288912.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2018 | RCV001265811.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Spondyloepimetaphyseal dysplasia with multiple dislocations
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894076.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Spondyloepimetaphyseal dysplasia with multiple dislocations
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV001426590.1
First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020 |
|
|
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Likely pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Spondyloepimetaphyseal dysplasia with multiple dislocations
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368665.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
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|
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Pathogenic
(Apr 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001832534.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
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Pathogenic
(Oct 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spondyloepimetaphyseal dysplasia with multiple dislocations
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512519.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP1 moderate, PP3 supporting
Geographic origin: Brazil
|
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Likely pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001443983.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic
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Pathogenic
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002242158.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 148 of the KIF22 protein (p.Pro148Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro148 amino acid residue in KIF22. Other variant(s) that disrupt this residue have been observed in individuals with KIF22-related conditions (PMID: 22152677), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF22 protein function. ClinVar contains an entry for this variant (Variation ID: 30334). This missense change has been observed in individual(s) with spondyloepimetaphyseal dysplasia with joint laxity (PMID: 22152677, 22152678, 25256152). 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. (less)
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Pathogenic
(May 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329964.9
First in ClinVar: Dec 06, 2016 Last updated: Sep 29, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency 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: 22152677, 25256152, 19277648, 22152678, 28229453, 30138938, 32860008, 27535533) (less)
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Pathogenic
(Dec 09, 2011)
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no assertion criteria provided
Method: literature only
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SPONDYLOEPIMETAPHYSEAL DYSPLASIA WITH JOINT LAXITY, TYPE 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044560.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 17, 2019 |
Comment on evidence:
In 2 unrelated Korean girls with spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2; 603546), 1 aged 4 years and 1, who was previously reported … (more)
In 2 unrelated Korean girls with spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2; 603546), 1 aged 4 years and 1, who was previously reported by Kim et al. (2009) ('patient 6'), aged 13 years, Min et al. (2011) identified heterozygosity for a 443C-T transition in exon 4 of the KIF22 gene, resulting in a pro148-to-leu (P148L) substitution that was predicted to interfere with ATP binding. The mutation was not found in unaffected family members or in 1,010 control chromosomes. In 4 affected members of an Italian family and 2 affected members of a UK family with SEMDJL2, as well as 5 sporadic patients from the US, Brazil, Germany, Japan, and Italy, respectively, Boyden et al. (2011) identified heterozygosity for the P148L mutation in the KIF22 gene. The mutation segregated with disease in each family, and was not found in 480 controls of European descent. (less)
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Pathogenic
(Sep 26, 2014)
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no assertion criteria provided
Method: literature only
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Spondyloepimetaphyseal dysplasia with multiple dislocations
Affected status: yes
Allele origin:
de novo
|
Yale Center for Mendelian Genomics, Yale University
Accession: SCV000987047.1
First in ClinVar: Aug 30, 2019 Last updated: Aug 30, 2019 |
|
Comment:
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP1 moderate, PP3 supporting
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 148 of the KIF22 protein (p.Pro148Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro148 amino acid residue in KIF22. Other variant(s) that disrupt this residue have been observed in individuals with KIF22-related conditions (PMID: 22152677), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF22 protein function. ClinVar contains an entry for this variant (Variation ID: 30334). This missense change has been observed in individual(s) with spondyloepimetaphyseal dysplasia with joint laxity (PMID: 22152677, 22152678, 25256152). 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.
Comment:
Not observed at significant frequency 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: 22152677, 25256152, 19277648, 22152678, 28229453, 30138938, 32860008, 27535533)
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:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP1 moderate, PP3 supporting
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 148 of the KIF22 protein (p.Pro148Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro148 amino acid residue in KIF22. Other variant(s) that disrupt this residue have been observed in individuals with KIF22-related conditions (PMID: 22152677), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF22 protein function. ClinVar contains an entry for this variant (Variation ID: 30334). This missense change has been observed in individual(s) with spondyloepimetaphyseal dysplasia with joint laxity (PMID: 22152677, 22152678, 25256152). 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.
Comment:
Not observed at significant frequency 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: 22152677, 25256152, 19277648, 22152678, 28229453, 30138938, 32860008, 27535533)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type: longitudinal observation of radiographic findings in a child heterozygous for a KIF22 mutation. | Tüysüz B | Pediatric radiology | 2015 | PMID: 25256152 |
| Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity. | Boyden ED | American journal of human genetics | 2011 | PMID: 22152678 |
| Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. | Min BJ | American journal of human genetics | 2011 | PMID: 22152677 |
| A distinct form of spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL)-leptodactylic type: radiological characteristics in seven new patients. | Kim OH | Skeletal radiology | 2009 | PMID: 19277648 |
Text-mined citations for rs193922921 ...
HelpThese 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 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.