The p.Asp45fs variant in ANO10 has been previously reported in 6 compound hetero zygous individuals and 2 homozygous individuals with adult-onset autosomal reces sive spinocerebellar ataxia (Renaud 2014, Balreira 2014, Fogel 2014, Minnerop 20 15). This variant has also been identified in 0.08% (12/14786) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs540331226). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency for autosomal recessive spinocerebellar ataxia. This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 162016). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 45 and leads to a premature termination codo n 9 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. In summary, the p.Asp45fs variant meets criteria to be c lassified as pathogenic for adult-onset autosomal recessive spinocerebellar atax ia. ACMG/AMP Criteria applied: PVS1; PM3_Strong.
ClinVar Genomic variation as it relates to human health
NM_018075.5(ANO10):c.132dup (p.Asp45fs)
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.
(19)
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
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018075.5(ANO10):c.132dup (p.Asp45fs)
Variation ID: 162016 Accession: VCV000162016.80
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 3p21.33 3: 43605720-43605721 (GRCh38) [ NCBI UCSC ] 3: 43647212-43647213 (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 1, 2016 Oct 26, 2024 Jul 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018075.5:c.132dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060545.3:p.Asp45fs frameshift NM_018075.5:c.132dupA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001204831.3:c.132dup NP_001191760.1:p.Asp45fs frameshift NM_001204832.3:c.132dup NP_001191761.1:p.Asp45fs frameshift NM_001204833.3:c.132dup NP_001191762.1:p.Asp45fs frameshift NM_001204834.3:c.132dup NP_001191763.1:p.Asp45fs frameshift NM_001346463.2:c.132dup NP_001333392.1:p.Asp45fs frameshift NM_001346464.2:c.132dup NP_001333393.1:p.Asp45fs frameshift NM_001346465.2:c.132dup NP_001333394.1:p.Asp45fs frameshift NM_001346466.2:c.132dup NP_001333395.1:p.Asp45fs frameshift NM_001346467.2:c.132dup NP_001333396.1:p.Asp45fs frameshift NM_001346468.2:c.132dup NP_001333397.1:p.Asp45fs frameshift NM_001346469.2:c.132dup NP_001333398.1:p.Asp45fs frameshift NM_018075.3:c.132_133insT NC_000003.12:g.43605729dup NC_000003.11:g.43647221dup NG_028216.2:g.90874dup - Protein change
- D45fs
- Other names
-
p.Asp45ArgfsX9
- Canonical SPDI
- NC_000003.12:43605720:TTTTTTTTT:TTTTTTTTTT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00060 (TTTTTTTTTT)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
- Comment on variant
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. |
|||
| ANO10 | - | - |
GRCh38 GRCh37 |
474 | 538 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000149437.28 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000311100.47 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 10, 2018 | RCV000825557.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001814069.3 |
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
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000862732.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: mixed
|
|
|
Pathogenic
(May 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive cerebellar ataxia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966877.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Asp45fs variant in ANO10 has been previously reported in 6 compound hetero zygous individuals and 2 homozygous individuals with adult-onset autosomal reces sive spinocerebellar … (more)
The p.Asp45fs variant in ANO10 has been previously reported in 6 compound hetero zygous individuals and 2 homozygous individuals with adult-onset autosomal reces sive spinocerebellar ataxia (Renaud 2014, Balreira 2014, Fogel 2014, Minnerop 20 15). This variant has also been identified in 0.08% (12/14786) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs540331226). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency for autosomal recessive spinocerebellar ataxia. This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 162016). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 45 and leads to a premature termination codo n 9 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. In summary, the p.Asp45fs variant meets criteria to be c lassified as pathogenic for adult-onset autosomal recessive spinocerebellar atax ia. ACMG/AMP Criteria applied: PVS1; PM3_Strong. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447379.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cerebellar ataxia (present)
Sex: male
|
|
|
Likely pathogenic
(May 26, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449599.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV001468025.1
First in ClinVar: Jan 05, 2021 Last updated: Jan 05, 2021 |
Comment on evidence:
PVS1, PS3
|
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormal central motor function
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755531.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
|
Pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002781522.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Feb 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000612337.5
First in ClinVar: Dec 06, 2016 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
|
|
|
Pathogenic
(Jun 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016415.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573055.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Frameshift variant is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162016 / PMID: 25089919). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Olivopontocerebellar atrophy (present) , Spastic ataxia (present)
|
|
|
Pathogenic
(Jan 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761460.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The ANO10 c.132dup variant is classified as Pathogenic (PVS1, PS4, PM3) This ANO10 c.132dup variant is located in exon 2/13 and is predicted to cause … (more)
The ANO10 c.132dup variant is classified as Pathogenic (PVS1, PS4, PM3) This ANO10 c.132dup variant is located in exon 2/13 and is predicted to cause a shift in the reading frame at codon 45. The variant has been reported in probands with a clinical presentation of OMIM:613728 (PS4). This variant is present at low frequency in population databases (PM2 not met). This variant has been detected in gnomAD 68 times, but consistently reported as pathogenic / likely pathogenic in the literature. This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). This variant has been reported in trans with other pathogenic variants PMID:25089919, 25182700 The variant has been reported in dbSNP (rs540331226) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162016) (less)
|
|
|
Pathogenic
(May 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329065.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest that the variant results in a significant reduction of ANO10 expression (Balreira et al., 2014); Frameshift variant predicted to result in … (more)
Published functional studies suggest that the variant results in a significant reduction of ANO10 expression (Balreira et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25664551, 27045840, 25133958, 25664549, 30515630, 31423897, 31980526, 25182700, 25089919, 29482223, 29915382) (less)
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001579504.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asp45Argfs*9) in the ANO10 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asp45Argfs*9) in the ANO10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO10 are known to be pathogenic (PMID: 25089919). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of cerebellar ataxia (PMID: 25089919, 25133958, 25182700). This variant is also known as c.123_124insA and c.132_133insT. ClinVar contains an entry for this variant (Variation ID: 162016). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004804468.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: ANO10 c.132dupA (p.Asp45ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ANO10 c.132dupA (p.Asp45ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.132dupA has been reported in the literature in multiple individuals affected with Spinocerebellar ataxia 10 (Bogdanova-Mihaylova_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30838263). ClinVar contains an entry for this variant (Variation ID: 162016). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249875.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
ANO10: PM3:Very Strong, PVS1, PM2
Number of individuals with the variant: 12
|
|
|
Uncertain significance
(Nov 01, 2014)
|
no assertion criteria provided
Method: literature only
|
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000196075.4
First in ClinVar: Dec 20, 2014 Last updated: Jan 08, 2022 |
Comment on evidence:
This variant, formerly titled SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 10, has been reclassified because of inconsistencies and/or errors in the numbering of variants based on the … (more)
This variant, formerly titled SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 10, has been reclassified because of inconsistencies and/or errors in the numbering of variants based on the cited reference sequence in the article by Balreira et al. (2014). In 2 unrelated women with autosomal recessive spinocerebellar ataxia-10 (SCAR10; 613728) and low to borderline CoQ10 levels in skeletal muscle, Balreira et al. (2014) identified compound heterozygous mutations in the ANO10 gene. Both patients carried a 1-bp insertion (c.132_133insT, NM_018075.3) in exon 2, resulting in a frameshift and premature termination (Asp45ArgfsTer53) on 1 allele. The second allele in 1 patient carried a c.1843G-A transition, resulting in an asp615-to-asn (D615N; rs238000380; 613726.0006) substitution at a conserved residue in the C terminus; the second allele in the other patient carried a c.1315G-T transversion in exon 6, resulting in a glu382-to-ter (E382X; 613726.0007) substitution. A heterozygous D615N change was found in 1 sample from the 1000 Genomes Project. The mutations in the first patient were found by whole-exome sequencing and were not found in her unaffected brother. The mutations in the second patient, which were found by direct sequencing of the ANO10 gene in 36 patients with low CoQ10 levels, segregated with the disorder in her family and were not found in 124 controls. Functional studies of the variants were not performed. NOTE: In the article by Balreira et al. (2014), the 1-bp insertion is given several times as c.132_133insT but as c.132_133insA in Figure 1c. In addition, the numbering of c.1315G-T does not correspond with the cited reference sequence. (less)
|
|
|
Pathogenic
(Dec 20, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965816.2
First in ClinVar: Aug 26, 2019 Last updated: Jan 03, 2022 |
|
|
|
Pathogenic
(Mar 24, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive spinocerebellar ataxia 10
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064548.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
The c.132dup variant results in an amino acid frameshift and creates a premature stop codon 9 amino acids downstream of the change, p.Asp45Argfs*9. This sequence … (more)
The c.132dup variant results in an amino acid frameshift and creates a premature stop codon 9 amino acids downstream of the change, p.Asp45Argfs*9. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ANO10 protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous states in individuals with cerebellar ataxia (PMIDs: 25089919, 29482223, 25133958, 25664549, 31423897, 29915382). Functional studies have demonstrated that this sequence change decreases the expression of ANO10 (PMID: 25182700). It has been described in the gnomAD database with a population frequency of 0.058% in non-Finnish European subpopulation (dbSNP rs540331226). These collective evidences indicate that c.132dup (p.Asp45Argfs*9) is pathogenic. (less)
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Autosomal recessive spinocerebellar ataxia 10
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005199972.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
Number of individuals with the variant: 2
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162016 / PMID: 25089919). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The ANO10 c.132dup variant is classified as Pathogenic (PVS1, PS4, PM3) This ANO10 c.132dup variant is located in exon 2/13 and is predicted to cause a shift in the reading frame at codon 45. The variant has been reported in probands with a clinical presentation of OMIM:613728 (PS4). This variant is present at low frequency in population databases (PM2 not met). This variant has been detected in gnomAD 68 times, but consistently reported as pathogenic / likely pathogenic in the literature. This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). This variant has been reported in trans with other pathogenic variants PMID:25089919, 25182700 The variant has been reported in dbSNP (rs540331226) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162016)
Comment:
Published functional studies suggest that the variant results in a significant reduction of ANO10 expression (Balreira et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25664551, 27045840, 25133958, 25664549, 30515630, 31423897, 31980526, 25182700, 25089919, 29482223, 29915382)
Comment:
This sequence change creates a premature translational stop signal (p.Asp45Argfs*9) in the ANO10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO10 are known to be pathogenic (PMID: 25089919). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of cerebellar ataxia (PMID: 25089919, 25133958, 25182700). This variant is also known as c.123_124insA and c.132_133insT. ClinVar contains an entry for this variant (Variation ID: 162016). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: ANO10 c.132dupA (p.Asp45ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.132dupA has been reported in the literature in multiple individuals affected with Spinocerebellar ataxia 10 (Bogdanova-Mihaylova_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30838263). ClinVar contains an entry for this variant (Variation ID: 162016). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ANO10: PM3:Very Strong, PVS1, PM2
Comment:
The c.132dup variant results in an amino acid frameshift and creates a premature stop codon 9 amino acids downstream of the change, p.Asp45Argfs*9. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ANO10 protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous states in individuals with cerebellar ataxia (PMIDs: 25089919, 29482223, 25133958, 25664549, 31423897, 29915382). Functional studies have demonstrated that this sequence change decreases the expression of ANO10 (PMID: 25182700). It has been described in the gnomAD database with a population frequency of 0.058% in non-Finnish European subpopulation (dbSNP rs540331226). These collective evidences indicate that c.132dup (p.Asp45Argfs*9) is pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
The p.Asp45fs variant in ANO10 has been previously reported in 6 compound hetero zygous individuals and 2 homozygous individuals with adult-onset autosomal reces sive spinocerebellar ataxia (Renaud 2014, Balreira 2014, Fogel 2014, Minnerop 20 15). This variant has also been identified in 0.08% (12/14786) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs540331226). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency for autosomal recessive spinocerebellar ataxia. This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 162016). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 45 and leads to a premature termination codo n 9 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. In summary, the p.Asp45fs variant meets criteria to be c lassified as pathogenic for adult-onset autosomal recessive spinocerebellar atax ia. ACMG/AMP Criteria applied: PVS1; PM3_Strong.
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162016 / PMID: 25089919). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The ANO10 c.132dup variant is classified as Pathogenic (PVS1, PS4, PM3) This ANO10 c.132dup variant is located in exon 2/13 and is predicted to cause a shift in the reading frame at codon 45. The variant has been reported in probands with a clinical presentation of OMIM:613728 (PS4). This variant is present at low frequency in population databases (PM2 not met). This variant has been detected in gnomAD 68 times, but consistently reported as pathogenic / likely pathogenic in the literature. This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). This variant has been reported in trans with other pathogenic variants PMID:25089919, 25182700 The variant has been reported in dbSNP (rs540331226) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162016)
Comment:
Published functional studies suggest that the variant results in a significant reduction of ANO10 expression (Balreira et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25664551, 27045840, 25133958, 25664549, 30515630, 31423897, 31980526, 25182700, 25089919, 29482223, 29915382)
Comment:
This sequence change creates a premature translational stop signal (p.Asp45Argfs*9) in the ANO10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO10 are known to be pathogenic (PMID: 25089919). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of cerebellar ataxia (PMID: 25089919, 25133958, 25182700). This variant is also known as c.123_124insA and c.132_133insT. ClinVar contains an entry for this variant (Variation ID: 162016). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: ANO10 c.132dupA (p.Asp45ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.132dupA has been reported in the literature in multiple individuals affected with Spinocerebellar ataxia 10 (Bogdanova-Mihaylova_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30838263). ClinVar contains an entry for this variant (Variation ID: 162016). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ANO10: PM3:Very Strong, PVS1, PM2
Comment:
The c.132dup variant results in an amino acid frameshift and creates a premature stop codon 9 amino acids downstream of the change, p.Asp45Argfs*9. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ANO10 protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous states in individuals with cerebellar ataxia (PMIDs: 25089919, 29482223, 25133958, 25664549, 31423897, 29915382). Functional studies have demonstrated that this sequence change decreases the expression of ANO10 (PMID: 25182700). It has been described in the gnomAD database with a population frequency of 0.058% in non-Finnish European subpopulation (dbSNP rs540331226). These collective evidences indicate that c.132dup (p.Asp45Argfs*9) is pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High Degree of Genetic Heterogeneity for Hereditary Cerebellar Ataxias in Australia. | Kang C | Cerebellum (London, England) | 2019 | PMID: 30078120 |
| Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. | Sun M | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29915382 |
| Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes. | Coutelier M | JAMA neurology | 2018 | PMID: 29482223 |
| Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship. | Bogdanova-Mihaylova P | Movement disorders clinical practice | 2016 | PMID: 30838263 |
| Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases. | Mallaret M | Journal of neurology | 2016 | PMID: 27142713 |
| Executive and Attentional Disorders, Epilepsy and Porencephalic Cyst in Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO10 Mutation. | Chamard L | European neurology | 2016 | PMID: 27045840 |
| Autosomal recessive cerebellar ataxia 3 due to homozygote c.132dupA mutation within the ANO10 gene--reply. | Koenig M | JAMA neurology | 2015 | PMID: 25664551 |
| Autosomal recessive cerebellar ataxia 3 due to homozygote c.132dupA mutation within the ANO10 gene. | Minnerop M | JAMA neurology | 2015 | PMID: 25664549 |
| ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency. | Balreira A | Journal of neurology | 2014 | PMID: 25182700 |
| Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. | Fogel BL | JAMA neurology | 2014 | PMID: 25133958 |
| Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. | Renaud M | JAMA neurology | 2014 | PMID: 25089919 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ANO10 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs540331226 ...
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 27, 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.
NCBI staff reviewed the sequence information reported in PubMed 25182700 Fig. 1A to determine the location of this allele on the current reference sequence.