This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 833 of the ANO5 protein (p.Met833Lys). This variant is present in population databases (rs142073798, gnomAD 0.1%). This missense change has been observed in individual(s) with limb girdle or distal muscular dystrophy (PMID: 23607914, 23663589, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285338). 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 expected to disrupt ANO5 protein function with a positive predictive value of 80%. This variant disrupts the p.Met833 amino acid residue in ANO5. Other variant(s) that disrupt this residue have been observed in individuals with ANO5-related conditions (PMID: 31350120), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_213599.3(ANO5):c.2498T>A (p.Met833Lys)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_213599.3(ANO5):c.2498T>A (p.Met833Lys)
Variation ID: 285338 Accession: VCV000285338.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p14.3 11: 22276177 (GRCh38) [ NCBI UCSC ] 11: 22297723 (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 Dec 6, 2016 Feb 28, 2024 Jan 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_213599.3:c.2498T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_998764.1:p.Met833Lys missense NM_001142649.2:c.2495T>A NP_001136121.1:p.Met832Lys missense NC_000011.10:g.22276177T>A NC_000011.9:g.22297723T>A NG_015844.1:g.88002T>A LRG_868:g.88002T>A LRG_868t1:c.2498T>A LRG_868p1:p.Met833Lys - Protein change
- M833K, M832K
- Other names
- -
- Canonical SPDI
- NC_000011.10:22276176:T:A
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00014
- 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. |
|||
| ANO5 | - | - |
GRCh38 GRCh37 |
1290 | 1326 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000347528.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 10, 2024 | RCV000645350.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 16, 2018 | RCV000778320.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 1, 2021 | RCV001729506.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2022 | RCV002502129.1 |
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
(Feb 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000338308.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 5
Sex: mixed
|
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Gnathodiaphyseal dysplasia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000767094.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 833 of the ANO5 protein (p.Met833Lys). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 833 of the ANO5 protein (p.Met833Lys). This variant is present in population databases (rs142073798, gnomAD 0.1%). This missense change has been observed in individual(s) with limb girdle or distal muscular dystrophy (PMID: 23607914, 23663589, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285338). 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 expected to disrupt ANO5 protein function with a positive predictive value of 80%. This variant disrupts the p.Met833 amino acid residue in ANO5. Other variant(s) that disrupt this residue have been observed in individuals with ANO5-related conditions (PMID: 31350120), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
ANO5-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914506.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ANO5 c.2498T>A (p.Met833Lys) missense variant has been reported in three studies in which it is found in three unrelated individuals affected with muscular dystrophy … (more)
The ANO5 c.2498T>A (p.Met833Lys) missense variant has been reported in three studies in which it is found in three unrelated individuals affected with muscular dystrophy who had high levels of creatine kinase, including one who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state with known or suspected null variants in trans (van der Kooi et al. 2013; Liewluck et al. 2013; Savarese et al. 2015). The p.Met833Lys variant was absent from 52 control individuals (Savarese et al. 2015) and present in a heterozygous state in three unaffected first-degree relatives of probands (van der Kooi et al. 2013; Liewluck et al. 2013). The p.Met833Lys variant is reported at a frequency of 0.001085 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the combined clinical evidence, the p.Met833Lys variant is classified as likely pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446906.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Muscular dystrophy (present)
Sex: male
|
|
|
Likely pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976687.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM3, PP2, PP3, PP5, BS2
|
|
|
Likely pathogenic
(Feb 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Gnathodiaphyseal dysplasia
Autosomal recessive limb-girdle muscular dystrophy type 2L Miyoshi muscular dystrophy 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811378.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001774111.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
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: 23663589, … (more)
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: 23663589, 25891276, 23607914, 30919934, 32528171, 29431110, 34426522, 34008892) (less)
|
|
|
Pathogenic
(May 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002771485.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal recessive limb-girdle muscular dystrophy. 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. Computational tools predict that this variant is damaging. (less)
|
|
|
Likely pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016459.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
Comment:
Comment:
The ANO5 c.2498T>A (p.Met833Lys) missense variant has been reported in three studies in which it is found in three unrelated individuals affected with muscular dystrophy who had high levels of creatine kinase, including one who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state with known or suspected null variants in trans (van der Kooi et al. 2013; Liewluck et al. 2013; Savarese et al. 2015). The p.Met833Lys variant was absent from 52 control individuals (Savarese et al. 2015) and present in a heterozygous state in three unaffected first-degree relatives of probands (van der Kooi et al. 2013; Liewluck et al. 2013). The p.Met833Lys variant is reported at a frequency of 0.001085 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the combined clinical evidence, the p.Met833Lys variant is classified as likely pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PM3, PP2, PP3, PP5, BS2
Comment:
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: 23663589, 25891276, 23607914, 30919934, 32528171, 29431110, 34426522, 34008892)
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal recessive limb-girdle muscular dystrophy. 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. Computational tools predict that this variant is damaging.
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 sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 833 of the ANO5 protein (p.Met833Lys). This variant is present in population databases (rs142073798, gnomAD 0.1%). This missense change has been observed in individual(s) with limb girdle or distal muscular dystrophy (PMID: 23607914, 23663589, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285338). 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 expected to disrupt ANO5 protein function with a positive predictive value of 80%. This variant disrupts the p.Met833 amino acid residue in ANO5. Other variant(s) that disrupt this residue have been observed in individuals with ANO5-related conditions (PMID: 31350120), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
The ANO5 c.2498T>A (p.Met833Lys) missense variant has been reported in three studies in which it is found in three unrelated individuals affected with muscular dystrophy who had high levels of creatine kinase, including one who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state with known or suspected null variants in trans (van der Kooi et al. 2013; Liewluck et al. 2013; Savarese et al. 2015). The p.Met833Lys variant was absent from 52 control individuals (Savarese et al. 2015) and present in a heterozygous state in three unaffected first-degree relatives of probands (van der Kooi et al. 2013; Liewluck et al. 2013). The p.Met833Lys variant is reported at a frequency of 0.001085 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the combined clinical evidence, the p.Met833Lys variant is classified as likely pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PM3, PP2, PP3, PP5, BS2
Comment:
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: 23663589, 25891276, 23607914, 30919934, 32528171, 29431110, 34426522, 34008892)
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal recessive limb-girdle muscular dystrophy. 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. Computational tools predict that this variant is damaging.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
| Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre. | Bugiardini E | Neuromuscular disorders : NMD | 2019 | PMID: 31561939 |
| Clinical and molecular findings in a cohort of ANO5-related myopathy. | Silva AMS | Annals of clinical and translational neurology | 2019 | PMID: 31353849 |
| Clinical spectrum and gene mutations in a Chinese cohort with anoctaminopathy. | Cai S | Neuromuscular disorders : NMD | 2019 | PMID: 31350120 |
| Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. | Ten Dam L | Clinical genetics | 2019 | PMID: 30919934 |
| The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. | Reuter MS | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2018 | PMID: 29431110 |
| Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. | Savarese M | Neuromuscular disorders : NMD | 2015 | PMID: 25891276 |
| ANO5-muscular dystrophy: clinical, pathological and molecular findings. | Liewluck T | European journal of neurology | 2013 | PMID: 23663589 |
| ANO5 mutations in the Dutch limb girdle muscular dystrophy population. | van der Kooi AJ | Neuromuscular disorders : NMD | 2013 | PMID: 23607914 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ANO5 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs142073798 ...
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 Sep 29, 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.