The Arg758Cys variant in ANO5 has been reported in >20 homozygous and compound heterozygous individuals with muscular dystrophy and was found to segregate with disease in 3 affected relatives (Bolduc 2010, Hicks 2011, Penttila 2010, Sarkozy 2012). This variant has been identified in 1% (2/186) of Finnish chromosomes by the 1000 Genomes Project (dbSNP rs157854529) and is a known Finnish founder variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the p.Arg758Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
ClinVar Genomic variation as it relates to human health
NM_213599.3(ANO5):c.2272C>T (p.Arg758Cys)
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.
(21)
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
21
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.2272C>T (p.Arg758Cys)
Variation ID: 2166 Accession: VCV000002166.62
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p14.3 11: 22274605 (GRCh38) [ NCBI UCSC ] 11: 22296151 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 May 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_213599.3:c.2272C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_998764.1:p.Arg758Cys missense NM_001142649.2:c.2269C>T NP_001136121.1:p.Arg757Cys missense NC_000011.10:g.22274605C>T NC_000011.9:g.22296151C>T NG_015844.1:g.86430C>T LRG_868:g.86430C>T LRG_868t1:c.2272C>T LRG_868p1:p.Arg758Cys Q75V66:p.Arg758Cys - Protein change
- R758C, R757C
- Other names
- -
- Canonical SPDI
- NC_000011.10:22274604:C:T
-
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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00009
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00045
The Genome Aggregation Database (gnomAD) 0.00049
The Genome Aggregation Database (gnomAD), exomes 0.00058
- 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
|
Nov 22, 2022 | RCV000002250.14 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2023 | RCV000032966.15 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
May 6, 2024 | RCV000128778.45 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV000811162.7 |
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
(Jul 28, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Limb-girdle muscular dystrophy, type 2L
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245577.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
Comment:
The Arg758Cys variant in ANO5 has been reported in >20 homozygous and compound heterozygous individuals with muscular dystrophy and was found to segregate with disease … (more)
The Arg758Cys variant in ANO5 has been reported in >20 homozygous and compound heterozygous individuals with muscular dystrophy and was found to segregate with disease in 3 affected relatives (Bolduc 2010, Hicks 2011, Penttila 2010, Sarkozy 2012). This variant has been identified in 1% (2/186) of Finnish chromosomes by the 1000 Genomes Project (dbSNP rs157854529) and is a known Finnish founder variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the p.Arg758Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227733.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 19
Sex: mixed
|
|
|
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: SCV001446828.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Elevated circulating creatine kinase concentration (present)
Sex: male
|
|
|
Pathogenic
(Jul 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581057.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM3_STR, PP1_MOD, PP3
|
Number of individuals with the variant: 2
Sex: female
|
|
|
Pathogenic
(Nov 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045791.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Myalgia (present) , Highly elevated creatine kinase (present) , Muscle spasm (present)
|
|
|
Pathogenic
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017059.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(May 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001770819.3
First in ClinVar: Aug 07, 2021 Last updated: Sep 16, 2024 |
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: 26886200, … (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: 26886200, 21739273, 37273706, 27911336, 24803842, 17132147, 31395899, 22980763, 21186264, 20096397, 30564623, 30919934, 25135358, 31341644, 28489263, 25891276, 22402862, 31589614, 34008892, 34418069, 35239206) (less)
|
|
|
Pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164480.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The homozygous p.Arg758Cys variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in … (more)
The homozygous p.Arg758Cys variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.06604% (182/275600) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137854529). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg758Cys variant in ANO5 has been reported in 26 individuals with ANO5-associated muscular dystrophy in the literature and segregated with disease in 4 affected relatives from 2 families (PMID: 27911336, 22402862, 21739273, 21186264, 20096397, 22980763). The presence of this variant in combination with 5 reported pathogenic (or likely pathogenic) variants and in 15 individuals with muscular dystrophy increases the likelihood that the p.Arg758Cys variant is pathogenic (PMID: 22980763). This variant has also been reported pathogenic in ClinVar (Variation ID: 2166). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on reports in ClinVar and multiple occurrences with reported pathogenic ANO5 variants in individuals with muscular dystrophy. ACMG/AMP Criteria applied: PM2, PP3, PP1_Moderate, PM3_VeryStrong (Richards 2015). (less)
|
|
|
Likely pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Miyoshi muscular dystrophy 3
Affected status: yes
Allele origin:
maternal
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976877.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM2, PM3, PP3, PP5
|
|
|
Pathogenic
(Jan 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520046.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment:
PP1, PP3, PM3_strong, PS4
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV004229883.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant is a common pathogenic variant associated with autosomal recessive muscular dystrophy and is considered a founder variant among individuals of Finnish ancestry (PMID: … (more)
This variant is a common pathogenic variant associated with autosomal recessive muscular dystrophy and is considered a founder variant among individuals of Finnish ancestry (PMID: 27911336, 22402862). Therefore, the frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of limb girdle muscular dystrophy and Miyoshi myopathy, 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)
|
|
|
Pathogenic
(Jan 22, 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: SCV000951415.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 758 of the ANO5 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 758 of the ANO5 protein (p.Arg758Cys). This variant is present in population databases (rs137854529, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy, distal myopathy and Miyoshi myopathy (PMID: 20096397, 21186264, 21739273, 22402862, 22980763, 24803842, 25135358, 27911336). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2166). 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 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503759.2
First in ClinVar: Apr 23, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace arginine with cysteine at codon 758 of the ANO5 protein (p.(Arg758Cys)). The arginine residue is invariant across species … (more)
This sequence change is predicted to replace arginine with cysteine at codon 758 of the ANO5 protein (p.(Arg758Cys)). The arginine residue is invariant across species (100 vertebrates, UCSC), and is located in the anoctamin domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.5% in the Finnish European population (rs137854529), and is recognised to be a Finnish founder mutation (PMID: 20096397, 22402862, 27911336; gnomAD v2.1.1 and v3.0). The frequency of the variant in the next most common population, European (non-Finnish), is 0.03%. This variant has been previously reported in affected individuals in homozygous state, and in heterozygous state along with another pathogenic variant (PM3_VeryStrong; PMID: 22402862, 21739273, 21186264, 22980763). It has been shown to segregate with disease in two affected siblings in the homozygous state (PP1; PMID: 20096397). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the variant classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PM3_VeryStrong, PP1, PP3. (less)
|
|
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Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247615.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
ANO5: PM3:Very Strong, PM2:Supporting, PP1, PP3
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Mar 20, 2012)
|
no assertion criteria provided
Method: literature only
|
MIYOSHI MUSCULAR DYSTROPHY 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022408.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 30, 2018 |
Comment on evidence:
In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (MMD3; 613319), Bolduc et al. (2010) identified a homozygous 2272C-T transition in exon 20 of the ANO5 … (more)
In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (MMD3; 613319), Bolduc et al. (2010) identified a homozygous 2272C-T transition in exon 20 of the ANO5 gene, resulting in an arg758-to-cys (R758C) substitution in a conserved residue in an extracellular loop. The R758C variant was not detected in 100 UK or 208 French Canadian control chromosomes, but was detected in 1 of 368 Finnish control chromosomes, indicating that this variant is present in the Finnish population at a low frequency. The family had originally been reported by Jaiswal et al. (2007). Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that R758C was the most common mutation, occurring in homozygous state in 9 Finnish patients and in heterozygous state with another pathogenic allele (see, e.g., 608662.0007 and 608662.0008) in 11 patients. The phenotype was highly variable: 2 females who were homozygous for the mutation had no clinical muscle weakness and only hyperCKemia, whereas other women with the mutation had myalgia and/or calf hypertrophy. Men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness (LGMDR12; 611307). The findings indicated that this mutation can be associated with a variety of muscle phenotypes. (less)
|
|
|
Pathogenic
(Mar 20, 2012)
|
no assertion criteria provided
Method: literature only
|
MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 12
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000809057.1
First in ClinVar: Sep 30, 2018 Last updated: Sep 30, 2018 |
Comment on evidence:
In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (MMD3; 613319), Bolduc et al. (2010) identified a homozygous 2272C-T transition in exon 20 of the ANO5 … (more)
In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (MMD3; 613319), Bolduc et al. (2010) identified a homozygous 2272C-T transition in exon 20 of the ANO5 gene, resulting in an arg758-to-cys (R758C) substitution in a conserved residue in an extracellular loop. The R758C variant was not detected in 100 UK or 208 French Canadian control chromosomes, but was detected in 1 of 368 Finnish control chromosomes, indicating that this variant is present in the Finnish population at a low frequency. The family had originally been reported by Jaiswal et al. (2007). Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that R758C was the most common mutation, occurring in homozygous state in 9 Finnish patients and in heterozygous state with another pathogenic allele (see, e.g., 608662.0007 and 608662.0008) in 11 patients. The phenotype was highly variable: 2 females who were homozygous for the mutation had no clinical muscle weakness and only hyperCKemia, whereas other women with the mutation had myalgia and/or calf hypertrophy. Men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness (LGMDR12; 611307). The findings indicated that this mutation can be associated with a variety of muscle phenotypes. (less)
|
|
|
Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Miyoshi muscular dystrophy 3
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142419.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_213599.2:c.2272C>T in the ANO5 gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. Sarkozy et al. reported two patients … (more)
NM_213599.2:c.2272C>T in the ANO5 gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. Sarkozy et al. reported two patients with Limb girdle muscular dystrophy type 2L harboring 2272C>T/191dupA (PMID: 22980763; PMID: 25135358). Bolduc et al reported a non-consanguineous Finnish patient suffering non-dysferlin Miyoshi myopathyharboing. The parents are carrier and two of their children are homozygous (PMID: 20096397). In addition, Penttila et al reported homozygous in 9 Finnish patients (PMID: 22402862). This variant is considered as a founder mutation in the Finnish population. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3_Strong; PP3, PP1. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739975.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955179.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
ANO5 @LOVD
Accession: SCV000172420.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Miyoshi muscular dystrophy 3
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000056224.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
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Comment:
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: 26886200, 21739273, 37273706, 27911336, 24803842, 17132147, 31395899, 22980763, 21186264, 20096397, 30564623, 30919934, 25135358, 31341644, 28489263, 25891276, 22402862, 31589614, 34008892, 34418069, 35239206)
Comment:
The homozygous p.Arg758Cys variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.06604% (182/275600) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137854529). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg758Cys variant in ANO5 has been reported in 26 individuals with ANO5-associated muscular dystrophy in the literature and segregated with disease in 4 affected relatives from 2 families (PMID: 27911336, 22402862, 21739273, 21186264, 20096397, 22980763). The presence of this variant in combination with 5 reported pathogenic (or likely pathogenic) variants and in 15 individuals with muscular dystrophy increases the likelihood that the p.Arg758Cys variant is pathogenic (PMID: 22980763). This variant has also been reported pathogenic in ClinVar (Variation ID: 2166). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on reports in ClinVar and multiple occurrences with reported pathogenic ANO5 variants in individuals with muscular dystrophy. ACMG/AMP Criteria applied: PM2, PP3, PP1_Moderate, PM3_VeryStrong (Richards 2015).
Comment:
PM2, PM3, PP3, PP5
Comment:
PP1, PP3, PM3_strong, PS4
Comment:
This variant is a common pathogenic variant associated with autosomal recessive muscular dystrophy and is considered a founder variant among individuals of Finnish ancestry (PMID: 27911336, 22402862). Therefore, the frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of limb girdle muscular dystrophy and Miyoshi myopathy, 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 758 of the ANO5 protein (p.Arg758Cys). This variant is present in population databases (rs137854529, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy, distal myopathy and Miyoshi myopathy (PMID: 20096397, 21186264, 21739273, 22402862, 22980763, 24803842, 25135358, 27911336). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2166). 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 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change is predicted to replace arginine with cysteine at codon 758 of the ANO5 protein (p.(Arg758Cys)). The arginine residue is invariant across species (100 vertebrates, UCSC), and is located in the anoctamin domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.5% in the Finnish European population (rs137854529), and is recognised to be a Finnish founder mutation (PMID: 20096397, 22402862, 27911336; gnomAD v2.1.1 and v3.0). The frequency of the variant in the next most common population, European (non-Finnish), is 0.03%. This variant has been previously reported in affected individuals in homozygous state, and in heterozygous state along with another pathogenic variant (PM3_VeryStrong; PMID: 22402862, 21739273, 21186264, 22980763). It has been shown to segregate with disease in two affected siblings in the homozygous state (PP1; PMID: 20096397). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the variant classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PM3_VeryStrong, PP1, PP3.
Comment:
ANO5: PM3:Very Strong, PM2:Supporting, PP1, PP3
Comment:
NM_213599.2:c.2272C>T in the ANO5 gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. Sarkozy et al. reported two patients with Limb girdle muscular dystrophy type 2L harboring 2272C>T/191dupA (PMID: 22980763; PMID: 25135358). Bolduc et al reported a non-consanguineous Finnish patient suffering non-dysferlin Miyoshi myopathyharboing. The parents are carrier and two of their children are homozygous (PMID: 20096397). In addition, Penttila et al reported homozygous in 9 Finnish patients (PMID: 22402862). This variant is considered as a founder mutation in the Finnish population. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3_Strong; PP3, PP1.
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 Arg758Cys variant in ANO5 has been reported in >20 homozygous and compound heterozygous individuals with muscular dystrophy and was found to segregate with disease in 3 affected relatives (Bolduc 2010, Hicks 2011, Penttila 2010, Sarkozy 2012). This variant has been identified in 1% (2/186) of Finnish chromosomes by the 1000 Genomes Project (dbSNP rs157854529) and is a known Finnish founder variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the p.Arg758Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
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: 26886200, 21739273, 37273706, 27911336, 24803842, 17132147, 31395899, 22980763, 21186264, 20096397, 30564623, 30919934, 25135358, 31341644, 28489263, 25891276, 22402862, 31589614, 34008892, 34418069, 35239206)
Comment:
The homozygous p.Arg758Cys variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.06604% (182/275600) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137854529). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg758Cys variant in ANO5 has been reported in 26 individuals with ANO5-associated muscular dystrophy in the literature and segregated with disease in 4 affected relatives from 2 families (PMID: 27911336, 22402862, 21739273, 21186264, 20096397, 22980763). The presence of this variant in combination with 5 reported pathogenic (or likely pathogenic) variants and in 15 individuals with muscular dystrophy increases the likelihood that the p.Arg758Cys variant is pathogenic (PMID: 22980763). This variant has also been reported pathogenic in ClinVar (Variation ID: 2166). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on reports in ClinVar and multiple occurrences with reported pathogenic ANO5 variants in individuals with muscular dystrophy. ACMG/AMP Criteria applied: PM2, PP3, PP1_Moderate, PM3_VeryStrong (Richards 2015).
Comment:
PM2, PM3, PP3, PP5
Comment:
PP1, PP3, PM3_strong, PS4
Comment:
This variant is a common pathogenic variant associated with autosomal recessive muscular dystrophy and is considered a founder variant among individuals of Finnish ancestry (PMID: 27911336, 22402862). Therefore, the frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of limb girdle muscular dystrophy and Miyoshi myopathy, 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 758 of the ANO5 protein (p.Arg758Cys). This variant is present in population databases (rs137854529, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy, distal myopathy and Miyoshi myopathy (PMID: 20096397, 21186264, 21739273, 22402862, 22980763, 24803842, 25135358, 27911336). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2166). 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 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change is predicted to replace arginine with cysteine at codon 758 of the ANO5 protein (p.(Arg758Cys)). The arginine residue is invariant across species (100 vertebrates, UCSC), and is located in the anoctamin domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.5% in the Finnish European population (rs137854529), and is recognised to be a Finnish founder mutation (PMID: 20096397, 22402862, 27911336; gnomAD v2.1.1 and v3.0). The frequency of the variant in the next most common population, European (non-Finnish), is 0.03%. This variant has been previously reported in affected individuals in homozygous state, and in heterozygous state along with another pathogenic variant (PM3_VeryStrong; PMID: 22402862, 21739273, 21186264, 22980763). It has been shown to segregate with disease in two affected siblings in the homozygous state (PP1; PMID: 20096397). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the variant classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PM3_VeryStrong, PP1, PP3.
Comment:
ANO5: PM3:Very Strong, PM2:Supporting, PP1, PP3
Comment:
NM_213599.2:c.2272C>T in the ANO5 gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. Sarkozy et al. reported two patients with Limb girdle muscular dystrophy type 2L harboring 2272C>T/191dupA (PMID: 22980763; PMID: 25135358). Bolduc et al reported a non-consanguineous Finnish patient suffering non-dysferlin Miyoshi myopathyharboing. The parents are carrier and two of their children are homozygous (PMID: 20096397). In addition, Penttila et al reported homozygous in 9 Finnish patients (PMID: 22402862). This variant is considered as a founder mutation in the Finnish population. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3_Strong; PP3, PP1.
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 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| ANO5 mutations in the Polish limb girdle muscular dystrophy patients: Effects on the protein structure. | Jarmula A | Scientific reports | 2019 | PMID: 31395899 |
| Clinical and molecular findings in a cohort of ANO5-related myopathy. | Silva AMS | Annals of clinical and translational neurology | 2019 | PMID: 31353849 |
| Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells. | Chandra G | Cell death discovery | 2019 | PMID: 31341644 |
| ANO5 Muscle Disease. | Adam MP | - | 2019 | PMID: 23193613 |
| Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
| Diagnostic anoctamin-5 protein defect in patients with ANO5-mutated muscular dystrophy. | Vihola A | Neuropathology and applied neurobiology | 2018 | PMID: 28489263 |
| Decreased Aerobic Capacity in ANO5-Muscular Dystrophy. | Ylikallio E | Journal of neuromuscular diseases | 2016 | PMID: 27911336 |
| Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. | Savarese M | Neuromuscular disorders : NMD | 2015 | PMID: 25891276 |
| Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
| Eosinophils in hereditary and inflammatory myopathies. | Schröder T | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2013 | PMID: 24803842 |
| Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression. | Witting N | Journal of neurology | 2013 | PMID: 23670307 |
| Muscle MRI findings in limb girdle muscular dystrophy type 2L. | Sarkozy A | Neuromuscular disorders : NMD | 2012 | PMID: 22980763 |
| Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. | Penttilä S | Neurology | 2012 | PMID: 22402862 |
| [Muscular dystrophy due to mutations in anoctamin 5: clinical and molecular genetic findings]. | Deschauer M | Der Nervenarzt | 2011 | PMID: 21739273 |
| A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy. | Hicks D | Brain : a journal of neurology | 2011 | PMID: 21186264 |
| A new distal myopathy with mutation in anoctamin 5. | Mahjneh I | Neuromuscular disorders : NMD | 2010 | PMID: 20692837 |
| Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. | Bolduc V | American journal of human genetics | 2010 | PMID: 20096397 |
| Patients with a non-dysferlin Miyoshi myopathy have a novel membrane repair defect. | Jaiswal JK | Traffic (Copenhagen, Denmark) | 2007 | PMID: 17132147 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ANO5 | - | - | - | - |
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Text-mined citations for rs137854529 ...
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Record last updated Oct 20, 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.