The c.191dupA pathogenic variant is previously described Founder mutation within the Northern European population (PMID: 21186264).
ClinVar Genomic variation as it relates to human health
NM_213599.3(ANO5):c.191dup (p.Asn64fs)
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.
(38)
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
38
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Genotype
- Identifiers
-
NM_213599.3(ANO5):c.191dup (p.Asn64fs)
Variation ID: 2164 Accession: VCV000002164.78
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 11p14.3 11: 22221100-22221101 (GRCh38) [ NCBI UCSC ] 11: 22242646-22242647 (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 Jul 23, 2014 Oct 26, 2024 Aug 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_213599.3:c.191dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_998764.1:p.Asn64fs frameshift NM_213599.3:c.191dupA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001142649.1:c.188dupA NM_001142649.2:c.188dup NP_001136121.1:p.Asn63fs frameshift NM_213599.2:c.191dupA NC_000011.10:g.22221107dup NC_000011.9:g.22242653dup NG_015844.1:g.32932dup LRG_868:g.32932dup - Protein change
- N63fs, N64fs
- Other names
- -
- Canonical SPDI
- NC_000011.10:22221100:AAAAAAA:AAAAAAAA
-
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.
- -
- 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 (10) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2024 | RCV000002248.33 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 20, 2012 | RCV000002247.11 | |
| Pathogenic (14) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000082844.61 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 2, 2015 | RCV000414931.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2017 | RCV000627021.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2022 | RCV001196017.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000627781.12 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Aug 29, 2018 | RCV000778317.11 | |
|
ANO5-related muscular dystrophy
|
Pathogenic (1) |
criteria provided, single submitter
|
Aug 2, 2023 | RCV003332991.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 21, 2021 | RCV002476911.4 | |
| Likely benign (1) |
no assertion criteria provided
|
Jan 1, 2019 | RCV001251667.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV002307353.5 | |
| click to load more click to collapse | ||||
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
(Jun 26, 2017)
|
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
Study: Broad Institute Center for Mendelian Genomics (CMG)
Accession: SCV000693897.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
The c.191dupA pathogenic variant is previously described Founder mutation within the Northern European population (PMID: 21186264).
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Oct 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
unknown
|
NeuroMeGen, Hospital Clinico Santiago de Compostela
Accession: SCV000882597.1
First in ClinVar: Feb 04, 2019 Last updated: Feb 04, 2019 |
|
|
|
Pathogenic
(Aug 29, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
ANO5-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914503.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ANO5 c.191dupA (p.Asn64LysfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the … (more)
The ANO5 c.191dupA (p.Asn64LysfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Asn64LysfsTer15 variant has been identified in at least 78 individuals with limb-girdle muscular dystrophy including 36 homozygotes and 42 compound heterozygotes; in two individuals with hyperCKemia in a compound heterozygous state; two individuals with myopathy, one in a homozygous state and one in a compound heterozygous state; three siblings with Miyoshi myopathy in a homozygous state; and eight individuals in a heterozygous state (Bolduc et al. 2010; Hicks et al. 2011; Deschauer et al. 2011; Penttiläet al. 2012; Magri et al. 2012; Sarkozy et al, 2013; Van der Kooi et al. 2013). The p.Asn64LysfsTer15 variant is reported as being one of the most common ANO5 pathogenic variants found in Northern European populations (Hicks et al., 2011). The p.Asn64LysfsTer15 variant has been reported in three of at least 500 control subjects and is reported at a frequency of 0.002186 in the population of the Exome Sequencing Project. Based on the potential impact of frameshift variants and collective evidence from the literature, the p.Asn64LysfsTer15 variant is classified as pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Aug 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000231252.4
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019
Comment:
The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et … (more)
The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et al. Hum Mutat. 2013 Aug;34(8):1111-8. AKT 4-29-16 (less)
|
Comment:
The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et … (more)
The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et al. Hum Mutat. 2013 Aug;34(8):1111-8. AKT 4-29-16 (less)
Number of individuals with the variant: 98
Sex: mixed
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Gnathodiaphyseal dysplasia
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518471.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Pathogenic
(Aug 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: SCV002581828.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM3, PP1
|
Number of individuals with the variant: 13
Sex: male
|
|
|
Pathogenic
(Oct 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600595.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: ANO5 c.191dupA (p.Asn64LysfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ANO5 c.191dupA (p.Asn64LysfsX15) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.304_308del [p.Lys102fs], c.835C>T [p.Arg279Ter]). The variant allele was found at a frequency of 0.0011 in 249002 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0011 vs 0.0047), allowing no conclusion about variant significance. c.191dupA has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Miyoshi Muscular Dystrophy, and Symptomatic/Asymptomatic HyperCKemia among other muscular disorders (e.g. Bolduc_2010, Savarese_2015, Papadopoulos_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twenty-one ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, one as likely pathogenic, and nineteen as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761826.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Jan 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149685.2
First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Myopathy (present) , Frequent falls (present) , Proximal muscle weakness (present)
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329066.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Observed in the heterozygous state without a second variant in multiple individuals from a cohort of patients with limb-girdle muscular dystrophy and/or Miyoshi muscular dystrophy … (more)
Observed in the heterozygous state without a second variant in multiple individuals from a cohort of patients with limb-girdle muscular dystrophy and/or Miyoshi muscular dystrophy type 3 and related disorders; however, patient-specific data was not provided (Savarese et al., 2015; Sarkozy et al., 2013); 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: 26810512, 25864073, 27142102, 26911675, 27708273, 24022920, 24843231, 23530687, 24232312, 21739273, 23607914, 22336395, 20096397, 23041008, 21186264, 26886200, 26913919, 30564623, 29794579, 30919934, 31395899, 31862442, 32403337, 31980526, 32399949, 31127727, 25891276, 34313030, 33837115, 23606453, 34106991, 31589614, 29417091, 32367299, 33258288, 25214167, 32819793, 33726816, 32528171, 32925086) (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841578.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.106%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.106%). This variant was 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 to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 22402862, 22980763, 23041008, 23606453, 25891276, 26886200, 27911336). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002164 / PMID: 20096397 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Elevated circulating creatine kinase concentration (present) , Myalgia (present) , Calf muscle hypertrophy (present)
|
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009730.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Aug 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ANO5-related muscular dystrophy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004041208.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714372.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP1, PP5, PM3, PS4, PVS1
Number of individuals with the variant: 9
|
|
|
Pathogenic
(Jun 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017103.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 30, 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: SCV000645880.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn64Lysfs*15) in the ANO5 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asn64Lysfs*15) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs575136178, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy 2L (LGMD2L) and ANO5-related conditions (PMID: 20096397, 21186264, 21739273, 23606453, 23607914, 25891276). It is commonly reported in individuals of Northern European ancestry (PMID: 20096397, 21186264, 21739273, 23607914). ClinVar contains an entry for this variant (Variation ID: 2164). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503669.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change in ANO5 is a frameshift variant predicted to cause a premature stop codon, p.(Asn64Lysfs*15), in biologically relevant exon 5/22 leading to nonsense-mediated … (more)
This sequence change in ANO5 is a frameshift variant predicted to cause a premature stop codon, p.(Asn64Lysfs*15), in biologically relevant exon 5/22 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.27% (3,169/1,176,516 alleles, 4 homozygotes) in the European (non-Finnish) population. The variant is recognised to be a Northern European founder mutation for ANO5-related muscle disease and has been detected in the homozygous and compound heterozygous state in multiple affected individuals (PMID: 21186264, 27708273, 25891276). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong. (less)
|
|
|
Pathogenic
(Aug 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Department of Human Genetics, Hannover Medical School
Accession: SCV005196403.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Clinical Features:
Hyporeflexia (present) , Elevated circulating creatine kinase concentration (present) , Myalgia (present) , EMG: myopathic abnormalities (present) , Calf muscle pseudohypertrophy (present) , Distal lower … (more)
Hyporeflexia (present) , Elevated circulating creatine kinase concentration (present) , Myalgia (present) , EMG: myopathic abnormalities (present) , Calf muscle pseudohypertrophy (present) , Distal lower limb muscle weakness (present) (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245645.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
ANO5: PM3:Very Strong, PVS1, PM2:Supporting
Number of individuals with the variant: 23
|
|
|
Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Myopathy
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492753.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Achilles tendon contracture
Elevated circulating creatine kinase concentration Lower limb amyotrophy Lower limb muscle weakness Polycystic kidney disease
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747724.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
|
|
|
Pathogenic
(Jul 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000255643.4
First in ClinVar: Oct 19, 2015 Last updated: Feb 15, 2018 |
|
|
|
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: SCV001448041.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Myopathy (present)
Sex: male
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Gnathodiaphyseal dysplasia
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366446.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM4,PP4,PP3.
|
|
|
Pathogenic
(Aug 21, 2021)
|
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: SCV002801207.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818219.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
|
Pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
germline
|
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005382149.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
ACMG Criteria: PVS1, PS4, PM3, PP5; Variant was found in heterozygous state.
Clinical Features:
Myopathy (present) , Mildly elevated creatine kinase (present) , Peripheral neuropathy (present) , Increased muscle fatiguability (present)
|
|
|
Pathogenic
(Mar 20, 2012)
|
no assertion criteria provided
Method: literature only
|
MIYOSHI MUSCULAR DYSTROPHY 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022405.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
Bolduc et al. (2010) found homozygosity for a 1-bp duplication (191dupA) in exon 5 of the ANO5 gene in a Dutch family with Miyoshi muscular … (more)
Bolduc et al. (2010) found homozygosity for a 1-bp duplication (191dupA) in exon 5 of the ANO5 gene in a Dutch family with Miyoshi muscular dystrophy-3 (MMD3; 613319) originally reported by Linssen et al. (1998) as family IV. The 191dupA mutation resulted in a frameshift and premature termination, consistent with a loss of function. It was absent in 210 French Canadian and 152 CEPH control chromosomes, but was identified in 1 of 100 UK and 2 of 210 Dutch control chromosomes. In a 63-year-old French Canadian woman with autosomal recessive limb-girdle muscular dystrophy type 2L (LGMDR12; 611307) and mild distal limb weakness, Bolduc et al. (2010) identified compound heterozygosity for 191dupA and a 692G-T transversion in exon 8 of the ANO5 gene, resulting in a gly231-to-val substitution (G231V; 608662.0005) in the intracellular N-terminal tail. The patient had late-onset asymmetric proximal upper limb and iliopsoas weakness and distal upper and lower limb weakness, as well as increased serum creatine kinase. Bolduc et al. (2010) noted that the phenotype overlapped between LGMD2L and Miyoshi myopathy. Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that 191dupA was the second most common mutation, occurring in the heterozygous state with another ANO5 mutation in 10 patients. The phenotype was highly variable: female mutation carriers had a mild disorder with myalgia and/or calf hypertrophy and hyperCKemia, whereas men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness. The findings indicated that this mutation can be associated with a variety of muscle phenotypes. Two Spanish brothers with LGMD2L were compound heterozygous for 191dupA and G231V. (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: SCV000809056.1
First in ClinVar: Sep 28, 2018 Last updated: Sep 28, 2018 |
Comment on evidence:
Bolduc et al. (2010) found homozygosity for a 1-bp duplication (191dupA) in exon 5 of the ANO5 gene in a Dutch family with Miyoshi muscular … (more)
Bolduc et al. (2010) found homozygosity for a 1-bp duplication (191dupA) in exon 5 of the ANO5 gene in a Dutch family with Miyoshi muscular dystrophy-3 (MMD3; 613319) originally reported by Linssen et al. (1998) as family IV. The 191dupA mutation resulted in a frameshift and premature termination, consistent with a loss of function. It was absent in 210 French Canadian and 152 CEPH control chromosomes, but was identified in 1 of 100 UK and 2 of 210 Dutch control chromosomes. In a 63-year-old French Canadian woman with autosomal recessive limb-girdle muscular dystrophy type 2L (LGMDR12; 611307) and mild distal limb weakness, Bolduc et al. (2010) identified compound heterozygosity for 191dupA and a 692G-T transversion in exon 8 of the ANO5 gene, resulting in a gly231-to-val substitution (G231V; 608662.0005) in the intracellular N-terminal tail. The patient had late-onset asymmetric proximal upper limb and iliopsoas weakness and distal upper and lower limb weakness, as well as increased serum creatine kinase. Bolduc et al. (2010) noted that the phenotype overlapped between LGMD2L and Miyoshi myopathy. Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that 191dupA was the second most common mutation, occurring in the heterozygous state with another ANO5 mutation in 10 patients. The phenotype was highly variable: female mutation carriers had a mild disorder with myalgia and/or calf hypertrophy and hyperCKemia, whereas men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness. The findings indicated that this mutation can be associated with a variety of muscle phenotypes. Two Spanish brothers with LGMD2L were compound heterozygous for 191dupA and G231V. (less)
|
|
|
Likely benign
(Jan 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability
Affected status: yes
Allele origin:
inherited
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427407.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925201.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927435.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974455.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(Aug 23, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2L
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011774.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
|
|
|
Pathogenic
(Dec 06, 2023)
|
no assertion criteria provided
Method: clinical testing
|
ANO5-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109121.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The ANO5 c.191dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn64Lysfs*15). This variant in the homozygous or compound heterozygous state … (more)
The ANO5 c.191dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn64Lysfs*15). This variant in the homozygous or compound heterozygous state has been reported in patients with autosomal recessive proximal limb-girdle muscular dystrophy or Miyoshi-like myopathy (Bolduc et al. 2010. PubMed ID: 20096397; Hicks et al. 2011. PubMed ID: 21186264; Bouquet et al. 2012. PubMed ID: 22336395). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in ANO5 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797445.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
ANO5 @LOVD
Accession: SCV000172417.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
ANO5-related disorder
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749728.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 10/28/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are … (more)
Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 10/28/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Myopia (present) , Abnormal skeletal muscle morphology (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Maternal teratogenic … (more)
Myopia (present) , Abnormal skeletal muscle morphology (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Maternal teratogenic exposure (present) (less)
Indication for testing: Diagnostic|Family Testing
Age: 60-69 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-11-11
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autoimmunity (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Hyperthyroidism (present) , Movement … (more)
Autoimmunity (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Hyperthyroidism (present) , Movement disorder (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-01-14
Testing laboratory interpretation: Pathogenic
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Myopia (present) , Feeding difficulties (present) , Abnormal stomach morphology (present) , Abnormal curvature of the vertebral column (present) , Anxiety (present) , Depression (present) … (more)
Myopia (present) , Feeding difficulties (present) , Abnormal stomach morphology (present) , Abnormal curvature of the vertebral column (present) , Anxiety (present) , Depression (present) , Motor stereotypies (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-10-28
Testing laboratory interpretation: Pathogenic
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The ANO5 c.191dupA (p.Asn64LysfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Asn64LysfsTer15 variant has been identified in at least 78 individuals with limb-girdle muscular dystrophy including 36 homozygotes and 42 compound heterozygotes; in two individuals with hyperCKemia in a compound heterozygous state; two individuals with myopathy, one in a homozygous state and one in a compound heterozygous state; three siblings with Miyoshi myopathy in a homozygous state; and eight individuals in a heterozygous state (Bolduc et al. 2010; Hicks et al. 2011; Deschauer et al. 2011; Penttiläet al. 2012; Magri et al. 2012; Sarkozy et al, 2013; Van der Kooi et al. 2013). The p.Asn64LysfsTer15 variant is reported as being one of the most common ANO5 pathogenic variants found in Northern European populations (Hicks et al., 2011). The p.Asn64LysfsTer15 variant has been reported in three of at least 500 control subjects and is reported at a frequency of 0.002186 in the population of the Exome Sequencing Project. Based on the potential impact of frameshift variants and collective evidence from the literature, the p.Asn64LysfsTer15 variant is classified as pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et al. Hum Mutat. 2013 Aug;34(8):1111-8. AKT 4-29-16
Comment:
Variant summary: ANO5 c.191dupA (p.Asn64LysfsX15) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.304_308del [p.Lys102fs], c.835C>T [p.Arg279Ter]). The variant allele was found at a frequency of 0.0011 in 249002 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0011 vs 0.0047), allowing no conclusion about variant significance. c.191dupA has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Miyoshi Muscular Dystrophy, and Symptomatic/Asymptomatic HyperCKemia among other muscular disorders (e.g. Bolduc_2010, Savarese_2015, Papadopoulos_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twenty-one ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, one as likely pathogenic, and nineteen as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Observed in the heterozygous state without a second variant in multiple individuals from a cohort of patients with limb-girdle muscular dystrophy and/or Miyoshi muscular dystrophy type 3 and related disorders; however, patient-specific data was not provided (Savarese et al., 2015; Sarkozy et al., 2013); 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: 26810512, 25864073, 27142102, 26911675, 27708273, 24022920, 24843231, 23530687, 24232312, 21739273, 23607914, 22336395, 20096397, 23041008, 21186264, 26886200, 26913919, 30564623, 29794579, 30919934, 31395899, 31862442, 32403337, 31980526, 32399949, 31127727, 25891276, 34313030, 33837115, 23606453, 34106991, 31589614, 29417091, 32367299, 33258288, 25214167, 32819793, 33726816, 32528171, 32925086)
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.106%). This variant was 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 to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 22402862, 22980763, 23041008, 23606453, 25891276, 26886200, 27911336). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002164 / PMID: 20096397 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PP1, PP5, PM3, PS4, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Asn64Lysfs*15) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs575136178, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy 2L (LGMD2L) and ANO5-related conditions (PMID: 20096397, 21186264, 21739273, 23606453, 23607914, 25891276). It is commonly reported in individuals of Northern European ancestry (PMID: 20096397, 21186264, 21739273, 23607914). ClinVar contains an entry for this variant (Variation ID: 2164). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in ANO5 is a frameshift variant predicted to cause a premature stop codon, p.(Asn64Lysfs*15), in biologically relevant exon 5/22 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.27% (3,169/1,176,516 alleles, 4 homozygotes) in the European (non-Finnish) population. The variant is recognised to be a Northern European founder mutation for ANO5-related muscle disease and has been detected in the homozygous and compound heterozygous state in multiple affected individuals (PMID: 21186264, 27708273, 25891276). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong.
Comment:
ANO5: PM3:Very Strong, PVS1, PM2:Supporting
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM4,PP4,PP3.
Comment:
ACMG Criteria: PVS1, PS4, PM3, PP5; Variant was found in heterozygous state.
Comment:
The ANO5 c.191dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn64Lysfs*15). This variant in the homozygous or compound heterozygous state has been reported in patients with autosomal recessive proximal limb-girdle muscular dystrophy or Miyoshi-like myopathy (Bolduc et al. 2010. PubMed ID: 20096397; Hicks et al. 2011. PubMed ID: 21186264; Bouquet et al. 2012. PubMed ID: 22336395). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in ANO5 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 10/28/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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 c.191dupA pathogenic variant is previously described Founder mutation within the Northern European population (PMID: 21186264).
Comment:
The ANO5 c.191dupA (p.Asn64LysfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Asn64LysfsTer15 variant has been identified in at least 78 individuals with limb-girdle muscular dystrophy including 36 homozygotes and 42 compound heterozygotes; in two individuals with hyperCKemia in a compound heterozygous state; two individuals with myopathy, one in a homozygous state and one in a compound heterozygous state; three siblings with Miyoshi myopathy in a homozygous state; and eight individuals in a heterozygous state (Bolduc et al. 2010; Hicks et al. 2011; Deschauer et al. 2011; Penttiläet al. 2012; Magri et al. 2012; Sarkozy et al, 2013; Van der Kooi et al. 2013). The p.Asn64LysfsTer15 variant is reported as being one of the most common ANO5 pathogenic variants found in Northern European populations (Hicks et al., 2011). The p.Asn64LysfsTer15 variant has been reported in three of at least 500 control subjects and is reported at a frequency of 0.002186 in the population of the Exome Sequencing Project. Based on the potential impact of frameshift variants and collective evidence from the literature, the p.Asn64LysfsTer15 variant is classified as pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et al. Hum Mutat. 2013 Aug;34(8):1111-8. AKT 4-29-16
Comment:
Variant summary: ANO5 c.191dupA (p.Asn64LysfsX15) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.304_308del [p.Lys102fs], c.835C>T [p.Arg279Ter]). The variant allele was found at a frequency of 0.0011 in 249002 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0011 vs 0.0047), allowing no conclusion about variant significance. c.191dupA has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Miyoshi Muscular Dystrophy, and Symptomatic/Asymptomatic HyperCKemia among other muscular disorders (e.g. Bolduc_2010, Savarese_2015, Papadopoulos_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twenty-one ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, one as likely pathogenic, and nineteen as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Observed in the heterozygous state without a second variant in multiple individuals from a cohort of patients with limb-girdle muscular dystrophy and/or Miyoshi muscular dystrophy type 3 and related disorders; however, patient-specific data was not provided (Savarese et al., 2015; Sarkozy et al., 2013); 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: 26810512, 25864073, 27142102, 26911675, 27708273, 24022920, 24843231, 23530687, 24232312, 21739273, 23607914, 22336395, 20096397, 23041008, 21186264, 26886200, 26913919, 30564623, 29794579, 30919934, 31395899, 31862442, 32403337, 31980526, 32399949, 31127727, 25891276, 34313030, 33837115, 23606453, 34106991, 31589614, 29417091, 32367299, 33258288, 25214167, 32819793, 33726816, 32528171, 32925086)
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.106%). This variant was 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 to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 22402862, 22980763, 23041008, 23606453, 25891276, 26886200, 27911336). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002164 / PMID: 20096397 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PP1, PP5, PM3, PS4, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Asn64Lysfs*15) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs575136178, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy 2L (LGMD2L) and ANO5-related conditions (PMID: 20096397, 21186264, 21739273, 23606453, 23607914, 25891276). It is commonly reported in individuals of Northern European ancestry (PMID: 20096397, 21186264, 21739273, 23607914). ClinVar contains an entry for this variant (Variation ID: 2164). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in ANO5 is a frameshift variant predicted to cause a premature stop codon, p.(Asn64Lysfs*15), in biologically relevant exon 5/22 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.27% (3,169/1,176,516 alleles, 4 homozygotes) in the European (non-Finnish) population. The variant is recognised to be a Northern European founder mutation for ANO5-related muscle disease and has been detected in the homozygous and compound heterozygous state in multiple affected individuals (PMID: 21186264, 27708273, 25891276). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong.
Comment:
ANO5: PM3:Very Strong, PVS1, PM2:Supporting
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM4,PP4,PP3.
Comment:
ACMG Criteria: PVS1, PS4, PM3, PP5; Variant was found in heterozygous state.
Comment:
The ANO5 c.191dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn64Lysfs*15). This variant in the homozygous or compound heterozygous state has been reported in patients with autosomal recessive proximal limb-girdle muscular dystrophy or Miyoshi-like myopathy (Bolduc et al. 2010. PubMed ID: 20096397; Hicks et al. 2011. PubMed ID: 21186264; Bouquet et al. 2012. PubMed ID: 22336395). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in ANO5 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 10/28/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Hyperckemia and myalgia are common presentations of anoctamin-5-related myopathy in French patients. | Papadopoulos C | Muscle & nerve | 2017 | PMID: 28187523 |
| The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. | Reddy HM | Journal of human genetics | 2017 | PMID: 27708273 |
| Decreased Aerobic Capacity in ANO5-Muscular Dystrophy. | Ylikallio E | Journal of neuromuscular diseases | 2016 | PMID: 27911336 |
| Utility of a next-generation sequencing-based gene panel investigation in German patients with genetically unclassified limb-girdle muscular dystrophy. | Kuhn M | Journal of neurology | 2016 | PMID: 26886200 |
| Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. | Savarese M | Neuromuscular disorders : NMD | 2015 | PMID: 25891276 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy. | Schneider I | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2014 | PMID: 24843231 |
| Macular dystrophy presenting in one of two siblings with limb-girdle muscular dystrophy type 2L due to mutation of ANO5. | Vaz-Pereira S | Eye (London, England) | 2014 | PMID: 24232312 |
| A case of progressive quadriceps weakness and elevated creatine kinase level mimicking inclusion body myositis. | Leung DG | Arthritis care & research | 2014 | PMID: 24022920 |
| ANO5 mutations in the Dutch limb girdle muscular dystrophy population. | van der Kooi AJ | Neuromuscular disorders : NMD | 2013 | PMID: 23607914 |
| ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation. | Sarkozy A | Human mutation | 2013 | PMID: 23606453 |
| Dilated cardiomyopathy in patients with mutations in anoctamin 5. | Wahbi K | International journal of cardiology | 2013 | PMID: 23041008 |
| Muscle MRI findings in limb girdle muscular dystrophy type 2L. | Sarkozy A | Neuromuscular disorders : NMD | 2012 | PMID: 22980763 |
| Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients. | Magri F | Neuromuscular disorders : NMD | 2012 | PMID: 22742934 |
| Novel ANO5 mutations causing hyper-CK-emia, limb girdle muscular weakness and Miyoshi type of muscular dystrophy. | Schessl J | Muscle & nerve | 2012 | PMID: 22499103 |
| Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. | Penttilä S | Neurology | 2012 | PMID: 22402862 |
| Miyoshi-like distal myopathy with mutations in anoctamin 5 gene. | Bouquet F | Revue neurologique | 2012 | PMID: 22336395 |
| Amyloidosis and exercise intolerance in ANO5 muscular dystrophy. | Milone M | Neuromuscular disorders : NMD | 2012 | PMID: 21820307 |
| Comparison of dysferlin expression in human skeletal muscle with that in monocytes for the diagnosis of dysferlin myopathy. | Gallardo E | PloS one | 2011 | PMID: 22194990 |
| [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 |
| 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 |
| Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. | Linssen WH | Neuromuscular disorders : NMD | 1998 | PMID: 9673985 |
| click to load more click to collapse | ||||
Text-mined citations for rs137854521 ...
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 Nov 10, 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.