ClinVar Genomic variation as it relates to human health
NM_213599.3(ANO5):c.2521C>G (p.His841Asp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Likely pathogenic(4); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_213599.3(ANO5):c.2521C>G (p.His841Asp)
Variation ID: 195705 Accession: VCV000195705.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p14.3 11: 22279544 (GRCh38) [ NCBI UCSC ] 11: 22301090 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Feb 28, 2024 Nov 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_213599.3:c.2521C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_998764.1:p.His841Asp missense NM_001142649.2:c.2518C>G NP_001136121.1:p.His840Asp missense NM_213599.2(ANO5):c.2521C>G NC_000011.10:g.22279544C>G NC_000011.9:g.22301090C>G NG_015844.1:g.91369C>G LRG_868:g.91369C>G LRG_868t1:c.2521C>G LRG_868p1:p.His841Asp - Protein change
- H841D, H840D
- Other names
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- Canonical SPDI
- NC_000011.10:22279543:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ANO5 | - | - |
GRCh38 GRCh37 |
1289 | 1325 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 7, 2021 | RCV000176339.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2019 | RCV000778321.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 16, 2023 | RCV000791570.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 29, 2020 | RCV001254725.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV003330536.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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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
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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
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 07, 2015)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329068.6
First in ClinVar: Dec 06, 2016 Last updated: Feb 15, 2018 |
Comment:
The H841D missense variant in the ANO5 gene has been reported previously in an individual with limb-girdle muscular dystrophy type 2L also known as, anoctaminopathy, … (more)
The H841D missense variant in the ANO5 gene has been reported previously in an individual with limb-girdle muscular dystrophy type 2L also known as, anoctaminopathy, who was heterozygous for this change and did not have another identifiable variant (Sarkozy et al., 2013). H841D was subsequently identified in an individual with limb-girdle muscular dystrophy type 2L who was compound heterozygous for H841D and another ANO5 variant(Leung et al., 2014). The H841D pathogenic variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this sequence change is probably damaging to the protein structure/function, and other missense variants in nearby residues (M833K, M839R) have been reported in the Human Gene Mutation Database in association with ANO5-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Given the available evidence, we interpret H841D as a pathogenic variant. (less)
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Likely pathogenic
(Sep 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331780.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 7
Sex: mixed
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Uncertain significance
(Jan 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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ANO5-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914507.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ANO5 c.2521C>G (p.His841Asp) missense variant has been reported in two studies in which it is found in a total of three patients, including one … (more)
The ANO5 c.2521C>G (p.His841Asp) missense variant has been reported in two studies in which it is found in a total of three patients, including one individual with suspected limb-girdle muscular dystrophy type 2L in a heterozygous state (Sarkozy et al. 2013) and two affected siblings in a compound heterozygous state (Leung et al. 2014). The p.His841Asp variant was observed in cis with a second variant that was predicted to be benign and in trans with a third known pathogenic variant in the two siblings. In addition, the p.His841Asp variant was present in cis with the second variant in a heterozygous state in one of the sibling's unaffected children (Leung et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.00009 in the Latino population of the Genome Aggregation Database. Based on the evidence, the ANO5 p.His841Asp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(May 29, 2020)
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criteria provided, single submitter
Method: research
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Limb-girdle muscular dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001430803.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
The p.His841Asp variant in ANO5 was identified by our study in 1 individual with limb-girdle muscular dystrophy, along with a variant of uncertain significance. The … (more)
The p.His841Asp variant in ANO5 was identified by our study in 1 individual with limb-girdle muscular dystrophy, along with a variant of uncertain significance. The variant in ANO5 has been reported in 4 individuals with limb-girdle muscular dystrophy, including the one from our study (PMID: 31395899, 24022920, 23606453). The presence of this variant in combination with a reported pathogenic variant, and in an individual with limb-girdle muscular dystrophy increases the likelihood that the p.His841Asp variant is pathogenic (Variation ID: 424764; PMID: 24022920). This variant has been identified in 0.009% (3/34378) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs781027702). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by GeneDx, likley pathogenic by Invitae and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, and as a variant of uncertain significance by Illumina Clinical Services Laboratory, Illumina (Variation ID:195705). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3 (Richards 2015). (less)
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Likely pathogenic
(Jul 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002771484.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Computational … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Computational tools predict that this variant is damaging. (less)
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Likely pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004037657.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: ANO5 c.2521C>G (p.His841Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ANO5 c.2521C>G (p.His841Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 249618 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4.8e-05 vs 0.0047), allowing no conclusion about variant significance. c.2521C>G has been reported in the literature in multiple compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g., Leung_2014, Jarmula_2019, Gonzalez-Quereda_2020, Segui_2020, Topf_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32403337, 31395899, 24022920, 23606453, 32528171, 32399949). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 2; likely pathogenic, n = 3, uncertain significance, n = 2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Sep 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021396.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000930827.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 841 of the ANO5 protein … (more)
This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 841 of the ANO5 protein (p.His841Asp). This variant is present in population databases (rs781027702, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 24022920, 31395899, 32403337). 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: 195705). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. | Gonzalez-Quereda L | Genes | 2020 | PMID: 32403337 |
Anoctamin 5 (ANO5) muscular dystrophy-three different phenotypes and a new histological pattern. | Seguí F | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2020 | PMID: 32399949 |
ANO5 mutations in the Polish limb girdle muscular dystrophy patients: Effects on the protein structure. | Jarmula A | Scientific reports | 2019 | PMID: 31395899 |
A case of progressive quadriceps weakness and elevated creatine kinase level mimicking inclusion body myositis. | Leung DG | Arthritis care & research | 2014 | PMID: 24022920 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ANO5 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0e539d12-07e8-4c3e-8df5-4404e203ee7d | - | - | - | - |
Text-mined citations for rs781027702 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.