chr11-22274605-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM5PP3PP5_Very_StrongBP4
The NM_213599.3(ANO5):c.2272C>T(p.Arg758Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000319 in 1,607,516 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R758H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_213599.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANO5 | NM_213599.3 | c.2272C>T | p.Arg758Cys | missense_variant | 20/22 | ENST00000324559.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO5 | ENST00000324559.9 | c.2272C>T | p.Arg758Cys | missense_variant | 20/22 | 1 | NM_213599.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000455 AC: 69AN: 151668Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000580 AC: 145AN: 250082Hom.: 0 AF XY: 0.000503 AC XY: 68AN XY: 135158
GnomAD4 exome AF: 0.000305 AC: 444AN: 1455736Hom.: 1 Cov.: 33 AF XY: 0.000311 AC XY: 225AN XY: 722916
GnomAD4 genome AF: 0.000455 AC: 69AN: 151780Hom.: 0 Cov.: 32 AF XY: 0.000634 AC XY: 47AN XY: 74150
ClinVar
Submissions by phenotype
not provided Pathogenic:9Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2023 | 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, 27911336, 24803842, 17132147, 31395899, 22980763, 21186264, 22402862, 20096397, 30564623, 30919934, 25135358, 31341644, 28489263, 25891276, 31589614, 34008892, 34418069, 35239206) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 28, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 12, 2022 | PP1, PP3, PM3_strong, PS4 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | ANO5: PM3:Very Strong, PM2:Supporting, PP1, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 13, 2023 | 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. - |
not provided, no classification provided | literature only | ANO5 @LOVD | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2014 | 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). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2012 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 25, 2022 | - - |
Miyoshi muscular dystrophy 3 Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2012 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PM2, PM3, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 22, 2022 | - - |
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | 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. - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at