rs137854523
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_213599.3(ANO5):c.692G>T(p.Gly231Val) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,613,328 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 4 hom. )
Consequence
ANO5
NM_213599.3 missense
NM_213599.3 missense
Scores
5
6
8
Clinical Significance
Conservation
PhyloP100: 5.82
Genes affected
ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PP5
Variant 11-22236206-G-T is Pathogenic according to our data. Variant chr11-22236206-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22236206-G-T is described in Lovd as [Pathogenic]. Variant chr11-22236206-G-T is described in Lovd as [Likely_pathogenic]. Variant chr11-22236206-G-T is described in Lovd as [Likely_pathogenic]. Variant chr11-22236206-G-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.07639387). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ANO5 | NM_213599.3 | c.692G>T | p.Gly231Val | missense_variant | 8/22 | ENST00000324559.9 | NP_998764.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ANO5 | ENST00000324559.9 | c.692G>T | p.Gly231Val | missense_variant | 8/22 | 1 | NM_213599.3 | ENSP00000315371.9 |
Frequencies
GnomAD3 genomes 0.000973 AC: 148AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00103 AC: 258AN: 250958Hom.: 1 AF XY: 0.000907 AC XY: 123AN XY: 135614
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GnomAD4 exome AF: 0.00135 AC: 1979AN: 1461104Hom.: 4 Cov.: 30 AF XY: 0.00125 AC XY: 911AN XY: 726886
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GnomAD4 genome 0.000972 AC: 148AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000820 AC XY: 61AN XY: 74434
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:26Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:11Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ANO5 p.G231V variant was identified as a compound heterozygous or homozygous variant in 17 of 1650 proband chromosomes (frequency: 0.01) from individuals with limb-girdle muscular dystrophy, hyperCKemia or mild dystrophic changes (Savarese_2015_PMID:25891276; Silva_2019_PMID:31353849; Bolduc_2010_PMID:20096397). The variant was identified in dbSNP (ID: rs137854523) and ClinVar (classified as pathogenic by GeneDx, Laboratory for Molecular Medicine and four other laboratories, and as likely pathogenic by Invitae and NeuroMeGen, Hospital Clinico Santiago de Compostela). The variant was identified in control databases in 274 of 282336 chromosomes (1 homozygous) at a frequency of 0.0009705 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 95 of 35372 chromosomes (freq: 0.002686), Other in 17 of 7204 chromosomes (freq: 0.00236), European (non-Finnish) in 152 of 128838 chromosomes (freq: 0.00118), Ashkenazi Jewish in 3 of 10360 chromosomes (freq: 0.00029), African in 5 of 24968 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25092 chromosomes (freq: 0.00008), but was not observed in the East Asian or South Asian populations. The p.Gly231 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| not provided, no classification provided | literature only | ANO5 @LOVD | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 22, 2023 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 29, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 02, 2023 | PM3_strong, PS4 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | ANO5: PM3:Very Strong, PM2:Supporting, BP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2024 | 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: 23193613, 22402862, 23670307, 26810512, 30564623, 30919934, 23047743, 22742934, 23041008, 25891276, 22980763, 20096397, 28489263, 31353849, 31931849, 34426522, 31589614, 34008892, 32403337, 35239206, 31980526, 32528171, 32399982, 33879512, 36913258, 23663589, 32367299, 32925086, 28176803, 23606453) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 21, 2023 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with limb girdle muscular dystrophy. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. - |
Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Dec 12, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Both dominant and recessive condition have been reported in this gene with no clear genotype and phenotype correlation (PMID: 25891276, PMID: 28176803). (N) 0200 - Variant is predicted to result in a missense amino acid change from a glycine to a valine (exon 8 of 22). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (272 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant is highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (dimerisation domain of Ca+-activated chloride-channel, anoctamin; PDB, NBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with ANO5-related myopathy, in a homozygous state or compound heterozygous with another variant (ClinVar, PMID: 31353849) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 15, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Feb 16, 2024 | This sequence variant is a single nucleotide substitution (G>T) at position 692 of the coding sequence of the ANO5 gene that results in a glycine to valine amino acid change at residue 231 of the anoctamin 5 protein. This is a previously reported variant (ClinVar 2165) that has been observed in homozygous or compound heterozygous state in many individuals and families affected by limb girdle muscular dystrophy and ANO5-related muscular disorders (PMID: 32367299, 31353849, 25891276, 23606453, 20096397, 22402862, 23041008, 22980763, 23663589, 23670307, 26810512, 30919934, 31931849, 32403337, 32528171). This variant is present in 2127 of 1613328 alleles (0.1318%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Gly231 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PP3, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002165, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 25891276, 22402862, 23606453, 22980763, PM3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000970, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 12, 2010 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | Oct 08, 2018 | - - |
ANO5-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The ANO5 c.692G>T (p.Gly231Val) missense variant has been reported in five studies in which it is found in a total of nine individuals with ANO5-Related Disorders, including in one individual in a homozygous state, in six individuals in a compound heterozygous state (including two siblings), in one individual in a heterozygous state in whom a second variant was not found, and in one individual in a heterozygous state as part of a complex allele with another missense variant (Bolduc et al. 2010; Wahbi et al. 2013; Penttilä et al. 2012; Sarkozy et al. 2012; Savarese et al. 2015). The p.Gly231Val variant was absent from 210 control chromosomes, but is reported at a frequency of 0.00402 in the Latino population of the Exome Aggregation Consortium. The Gly231 residue is conserved. Based on the collective evidence the p.Gly231Val 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 05, 2024 | The ANO5 c.692G>T variant is predicted to result in the amino acid substitution p.Gly231Val. This variant has been reported in several unrelated individuals to be causative for limb girdle muscular dystrophy 2L (Bolduc et al. 2010. PubMed ID: 20096397; Wahbi et al. 2013. PubMed ID: 23041008; Savarese et al. 2015. PubMed ID: 25891276). In addition, we have seen this variant in the homozygous and compound heterozygous state in other patients at PreventionGenetics with muscular dystrophy. This variant is reported in 0.27% of alleles in individuals of Latino descent in gnomAD. In summary, we categorize the c.692G>T variant as pathogenic for autosomal recessive ANO5-related disorders. - |
Miyoshi muscular dystrophy 3 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change in ANO5 is predicted to replace glycine with valine at codon 231, p.(Gly231Val). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in a cytoplasmic domain. There is a large physicochemical difference between glycine and valine. The highest population minor allele frequency in gnomAD v2.1 is 0.3% (95/35,372 alleles, 1 homozygote) in the Latino/admixed American population. This variant has been detected as homozygous or compound heterozygous with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy, hyperCKaemia, and pseudo-metabolic myopathy phenotypes. The variants were confirmed in trans by parental testing in at least one of the compound heterozygous individuals (PMID: 20096397, 31353849). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong. - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2024 | Variant summary: ANO5 c.692G>T (p.Gly231Val) results in a non-conservative amino acid change located in the Anoctamin, dimerisation domain (IPR032394) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 250958 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.001 vs 0.0047), allowing no conclusion about variant significance. c.692G>T has been reported in the literature in multiple bi-allelic individuals affected with muscular dystrophy type 2 (LGMD2), Miyoshi-like muscle dystrophy, and hyperCKemia (examples: Bolduc_2010, Wahbi_2013, Savarese_2015, TenDam_2019, and Gonzalez-Quereda_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20096397, 23041008, 30919934, 32403337, 25891276). ClinVar contains an entry for this variant (Variation ID: 2165). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary fructosuria Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 30, 2018 | The p.Gly231Val variant in ANO5 has been previously reported in at least 15 comp ound heterozygous and 1 homozygous individuals with ANO5-related muscle diseases , ranging from asymptomatic hyperCKemia to limb-girdle muscular dystrophy type 2L (LGMD2L) or Miyoshi muscular dystrophy, and segregated with disease in one co mpound heterozygous sibling. Three of these individuals were female and presente d with asymptomatic hyperCKemia (Bolduc 2010, Wahbi 2013, Savarese 2015, Penttil a 2012, Witting 2013, Liewluck 2013, Sarkozy 2013). Typically, females have mil der disease manifestations than males (Bolduc 2010, Penttila 2012). This variant has also been reported in ClinVar (Variation ID 2165) and identified in 0.113% (143/126350) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the g eneral population, its frequency is low enough to be consistent with the disease prevalence. Computational prediction tools and conservation analysis suggest th at the p.Gly231Val variant may impact the protein. In summary, this variant meet s criteria to be classified as pathogenic for ANO5-related muscle diseases in an autosomal recessive manner based upon proband count. ACMG/AMP Criteria applied: PP3, PP1, PM3_Very Strong. - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 231 of the ANO5 protein (p.Gly231Val). This variant is present in population databases (rs137854523, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy type 2 (LGMD2), Miyoshi-like muscle dystrophy, and hyperCKemia (PMID: 20096397, 22402862, 22980763, 23041008, 23606453, 23670307, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2165). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO5 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Uncertain
T
Polyphen
D
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T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at