rs575136178

Variant names:

• chr11-22221100-C-CA
• rs137854521
• NM_213599.3:c.191dupA

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP1_Strong PP4 PM3 PVS1

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.191dup (p.Asn64LysfsTer15) variant in ANO5 is a frameshift variant observed to cause a premature stop codon in biologically relevant exon 5/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1; PMID:20096397). This variant has been detected in at least 26 individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least eight patients (1.0 pt, PMID:20096397, 28187523, 30919934; PM3). At least one patient with this variant displayed progressive proximal muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in 4 affected family members from 3 families (PP1_Strong; PMID:22336395, 20096397, 28187523). The filtering allele frequency of this variant is 0.001770 (the lower threshold of the 95% CI of 139/67894 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (>0.002) for BS1; however, this variant is a frequently observed variant among affected patients and the VCEP opted not to apply this code (BS1 exception). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115378/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: ANO5 NM_213599.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:37 B:1 O:2
• Conservation: PhyloP100: 2.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3	c.191dupA	p.Asn64LysfsTer15	frameshift_variant	Exon 5 of 22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.191dupA	p.Asn64LysfsTer15	frameshift_variant	Exon 5 of 22	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 151826 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00110 AC: 273 AN: 249002 Hom.: 2 AF XY: 0.00110 AC XY: 148 AN XY: 134624

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00218 AC: 3171 AN: 1457112 Hom.: 4 Cov.: 29 AF XY: 0.00217 AC XY: 1572 AN XY: 725068

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.000653

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00118 AC: 179 AN: 151944 Hom.: 0 Cov.: 33 AF XY: 0.00104 AC XY: 77 AN XY: 74266

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00205

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.00117

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37 Benign:1 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2024	PP1, PP5, PM3, PS4, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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	Eurofins Ntd Llc (ga)	Aug 08, 2016	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 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ANO5: PM3:Very Strong, PVS1, PM2:Supporting -

Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 20, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Aug 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Miyoshi muscular dystrophy (MIM#613319) and muscular dystrophy, limb-girdle (MIM#611307). The mechanism behind gnathodiaphyseal dysplasia (MIM#166260) remains unknown (PMID: 32112655). (I) 0108 - This gene is associated with both recessive and dominant disease. Only missense variants have been reported for gnathodiaphyseal dysplasia (MIM#166260). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 22402862). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 294 heterozygotes, 2 homozygotes). It is a known founder mutation of the Northern European population (PMID: 21186264). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with ANO5-myopathy and has been reported in homozygotes and compound heterozygotes. It has been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 25891276, 31353849). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Nov 29, 2022	ACMG Criteria: PVS1, PS4, PM3, PP5; Variant was found in heterozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 26, 2017	The c.191dupA pathogenic variant is previously described Founder mutation within the Northern European population (PMID: 21186264). -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 05, 2024	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. -
Pathogenic, reviewed by expert panel	curation	ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	Jan 09, 2025	The NM_213599.3: c.191dup (p.Asn64LysfsTer15) variant in ANO5 is a frameshift variant observed to cause a premature stop codon in biologically relevant exon 5/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1; PMID: 20096397). This variant has been detected in at least 26 individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least eight patients (1.0 pt, PMID: 20096397, 28187523, 30919934; PM3). At least one patient with this variant displayed progressive proximal muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in 4 affected family members from 3 families (PP1_Strong; PMID: 22336395, 20096397, 28187523). The filtering allele frequency of this variant is 0.001770 (the lower threshold of the 95% CI of 139/67894 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (>0.002) for BS1; however, this variant is a frequently observed variant among affected patients and the VCEP opted not to apply this code (BS1 exception). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PP1_Strong. -

ANO5-related disorder Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2018	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. -

Gnathodiaphyseal dysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM4,PP4,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Miyoshi muscular dystrophy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 20, 2012

- -

ANO5-related muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2023

- -

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

Feb 05, 2024

- -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2025

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. -

Myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 02, 2015

- -

Polycystic kidney disease;C0241005:Elevated circulating creatine kinase concentration;C0410264:Achilles tendon contracture;C1836296:Lower limb muscle weakness;C4024921:Lower limb amyotrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854521; hg19: chr11-22242646;