ClinVar Genomic variation as it relates to human health
NM_001159773.2(CANT1):c.676G>A (p.Val226Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001159773.2(CANT1):c.676G>A (p.Val226Met)
Variation ID: 31018 Accession: VCV000031018.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 78995177 (GRCh38) [ NCBI UCSC ] 17: 76991259 (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 Dec 15, 2018 Mar 30, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001159773.2:c.676G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001153245.1:p.Val226Met missense NM_001159772.2:c.676G>A NP_001153244.1:p.Val226Met missense NM_138793.3:c.676G>A NM_138793.4:c.676G>A NP_620148.1:p.Val226Met missense NC_000017.11:g.78995177C>T NC_000017.10:g.76991259C>T NG_016645.1:g.19641G>A Q8WVQ1:p.Val226Met - Protein change
- V226M
- Other names
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- Canonical SPDI
- NC_000017.11:78995176: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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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CANT1 | - | - |
GRCh38 GRCh37 |
391 | 425 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000024010.8 | |
Pathogenic (1) |
no assertion criteria provided
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May 1, 2011 | RCV000509573.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2023 | RCV001380267.5 |
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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Likely pathogenic
(Feb 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004025733.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with loss of enzymatic function (Furuichi et al., 2011); In silico analysis supports that this missense variant has … (more)
Published functional studies demonstrate a damaging effect with loss of enzymatic function (Furuichi et al., 2011); 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: 21412251, 30949876, 21037275, 28742282) (less)
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001578265.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the CANT1 protein (p.Val226Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the CANT1 protein (p.Val226Met). This variant is present in population databases (rs377546036, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive Desbuquois dysplasia ("Kim-variant") or multiple epiphyseal dysplasia (PMID: 21037275, 28742282). ClinVar contains an entry for this variant (Variation ID: 31018). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CANT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CANT1 function (PMID: 21037275). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Desbuquois dysplasia 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518636.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Desbuquois dysplasia 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004804085.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: CANT1 c.676G>A (p.Val226Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CANT1 c.676G>A (p.Val226Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251052 control chromosomes (gnomAD). c.676G>A has been reported in the literature in multiple individuals affected with Desbuquois dysplasia or Multiple Epiphyseal Dysplasia (Furuichi_2011, Balasubramanian_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a substantial reduction of normal nucleotidase activity (Furuichi_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21037275, 28742282). ClinVar contains an entry for this variant (Variation ID: 31018). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 01, 2011)
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no assertion criteria provided
Method: literature only
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DESBUQUOIS DYSPLASIA 1, KIM VARIANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045301.7
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Desbuquois Dysplasia 1, Kim Variant In a Japanese patient, born of consanguineous parents, with the Kim variant of Desbuquois dysplasia-1 (DBQD1; see 251450), Furuichi et … (more)
Desbuquois Dysplasia 1, Kim Variant In a Japanese patient, born of consanguineous parents, with the Kim variant of Desbuquois dysplasia-1 (DBQD1; see 251450), Furuichi et al. (2011) identified a homozygous 676G-A transition in the CANT1 gene, resulting in a val226-to-met (V226M) substitution in a highly conserved residue. Four additional patients, of Japanese or Korean origin, with this phenotype also carried the V226M substitution in compound heterozygosity with another pathogenic mutation in the CANT1 gene (see, e.g., 613165.0014). The V226M mutation was found in 1 of 754 Japanese controls and in 1 of 187 Korean controls. Four of the 5 patients had been reported by Kim et al. (2010) as having a milder form of the disorder. All had normal cognitive development, but most showed delayed motor development. All had short stature and multiple joint dislocations and laxity, particularly affecting the knee. Radiographic criteria included a 'monkey wrench' appearance of the proximal femora, epimetaphyseal dysplasia at the knees, and advanced carpal/tarsal bone age. Radiographic studies showed short metacarpals with normal or slightly elongated proximal and middle phalanges and short distal phalanges, resulting in a nearly equal length of the second to fourth or fifth finger. None had an accessory ossification center or thumb anomalies. After about age 15 years, radiographs showed precocious degenerative arthritis in the carpal bones and interphalangeal joints. The hip joints showed premature degenerative osteoarthritis with age. All patients also had kyphoscoliosis with vertebral endplate irregularities and narrowing of the disc space; the older ones developed progressive degenerative spondylosis. In vitro functional expression studies in COS-7 cells showed that the V226M mutant protein was stably expressed and secreted normally, but had decreased enzyme activity compared to wildtype. The findings indicated that the so-called Kim variant of DBQD is allelic to types 1 and 2 DBQD. By haplotype analysis of the 5 families with the V226M mutation reported by Furuichi et al. (2011), Dai et al. (2011) demonstrated a founder effect for this mutation among Japanese and Korean individuals. The age of the mutation was estimated at about 1,420 years, around the time of the late Kofun era. Epiphyseal Dysplasia, Multiple, 7 In a female patient of Latino origin (R01-152A) with multiple epiphyseal dysplasia (EDM7; 617719), Balasubramanian et al. (2017) identified homozygosity for the V226M mutation in the CANT1 gene. The authors stated that although radiographs of the EDM patient showed some overlapping features with DBQD, the overall phenotype was milder and clearly distinct from DBQD. They noted that 1 previously reported family with the Kim variant of DBQD was also homozygous for V226M (Furuichi et al., 2011), but stated that radiographic data for a full comparison of the phenotype with their EDM case had not been published. (less)
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Pathogenic
(May 01, 2011)
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no assertion criteria provided
Method: literature only
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EPIPHYSEAL DYSPLASIA, MULTIPLE, 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000607726.2
First in ClinVar: Oct 19, 2017 Last updated: Dec 15, 2018 |
Comment on evidence:
Desbuquois Dysplasia 1, Kim Variant In a Japanese patient, born of consanguineous parents, with the Kim variant of Desbuquois dysplasia-1 (DBQD1; see 251450), Furuichi et … (more)
Desbuquois Dysplasia 1, Kim Variant In a Japanese patient, born of consanguineous parents, with the Kim variant of Desbuquois dysplasia-1 (DBQD1; see 251450), Furuichi et al. (2011) identified a homozygous 676G-A transition in the CANT1 gene, resulting in a val226-to-met (V226M) substitution in a highly conserved residue. Four additional patients, of Japanese or Korean origin, with this phenotype also carried the V226M substitution in compound heterozygosity with another pathogenic mutation in the CANT1 gene (see, e.g., 613165.0014). The V226M mutation was found in 1 of 754 Japanese controls and in 1 of 187 Korean controls. Four of the 5 patients had been reported by Kim et al. (2010) as having a milder form of the disorder. All had normal cognitive development, but most showed delayed motor development. All had short stature and multiple joint dislocations and laxity, particularly affecting the knee. Radiographic criteria included a 'monkey wrench' appearance of the proximal femora, epimetaphyseal dysplasia at the knees, and advanced carpal/tarsal bone age. Radiographic studies showed short metacarpals with normal or slightly elongated proximal and middle phalanges and short distal phalanges, resulting in a nearly equal length of the second to fourth or fifth finger. None had an accessory ossification center or thumb anomalies. After about age 15 years, radiographs showed precocious degenerative arthritis in the carpal bones and interphalangeal joints. The hip joints showed premature degenerative osteoarthritis with age. All patients also had kyphoscoliosis with vertebral endplate irregularities and narrowing of the disc space; the older ones developed progressive degenerative spondylosis. In vitro functional expression studies in COS-7 cells showed that the V226M mutant protein was stably expressed and secreted normally, but had decreased enzyme activity compared to wildtype. The findings indicated that the so-called Kim variant of DBQD is allelic to types 1 and 2 DBQD. By haplotype analysis of the 5 families with the V226M mutation reported by Furuichi et al. (2011), Dai et al. (2011) demonstrated a founder effect for this mutation among Japanese and Korean individuals. The age of the mutation was estimated at about 1,420 years, around the time of the late Kofun era. Epiphyseal Dysplasia, Multiple, 7 In a female patient of Latino origin (R01-152A) with multiple epiphyseal dysplasia (EDM7; 617719), Balasubramanian et al. (2017) identified homozygosity for the V226M mutation in the CANT1 gene. The authors stated that although radiographs of the EDM patient showed some overlapping features with DBQD, the overall phenotype was milder and clearly distinct from DBQD. They noted that 1 previously reported family with the Kim variant of DBQD was also homozygous for V226M (Furuichi et al., 2011), but stated that radiographic data for a full comparison of the phenotype with their EDM case had not been published. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1. | Balasubramanian K | American journal of medical genetics. Part A | 2017 | PMID: 28742282 |
A founder mutation of CANT1 common in Korean and Japanese Desbuquois dysplasia. | Dai J | Journal of human genetics | 2011 | PMID: 21412251 |
CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant. | Furuichi T | Journal of medical genetics | 2011 | PMID: 21037275 |
A variant of Desbuquois dysplasia characterized by advanced carpal bone age, short metacarpals, and elongated phalanges: report of seven cases. | Kim OH | American journal of medical genetics. Part A | 2010 | PMID: 20358597 |
Text-mined citations for rs377546036 ...
HelpRecord last updated Apr 06, 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.