Submissions for variant NM_213599.3(ANO5):c.191dup (p.Asn64fs)

dbSNP: rs137854521

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	RCV002307353	SCV005620274	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2025-01-09	reviewed by expert panel	curation	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.
Eurofins Ntd Llc (ga)	RCV000082844	SCV000231252	pathogenic	not provided	2016-08-08	criteria provided, single submitter	clinical testing	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
Athena Diagnostics	RCV000082844	SCV000255643	pathogenic	not provided	2017-07-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000082844	SCV000329066	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	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)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414931	SCV000492753	pathogenic	Myopathy	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627781	SCV000645880	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2025-01-24	criteria provided, single submitter	clinical testing	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000002248	SCV000693897	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2017-06-26	criteria provided, single submitter	research	The c.191dupA pathogenic variant is previously described Founder mutation within the Northern European population (PMID: 21186264).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000627021	SCV000747724	pathogenic	Elevated circulating creatine kinase concentration; Polycystic kidney disease; Achilles tendon contracture; Lower limb amyotrophy; Lower limb muscle weakness	2017-01-01	criteria provided, single submitter	clinical testing
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000002248	SCV000882597	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2018-10-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778317	SCV000914503	pathogenic	ANO5-related disorder	2018-08-29	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000002248	SCV001149685	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2021-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082844	SCV001245645	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ANO5: PM3:Very Strong, PVS1, PM2:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196017	SCV001366446	pathogenic	Gnathodiaphyseal dysplasia	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM4,PP4,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000082844	SCV001448041	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000082844	SCV001714372	pathogenic	not provided	2024-08-13	criteria provided, single submitter	clinical testing	PP1, PP5, PM3, PS4, PVS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000082844	SCV002009730	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000082844	SCV002017103	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002307353	SCV002503669	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-02-05	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV001196017	SCV002518471	pathogenic	Gnathodiaphyseal dysplasia	2022-05-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002248	SCV002581828	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2022-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307353	SCV002600595	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-10-19	criteria provided, single submitter	clinical testing	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.
Genetics and Molecular Pathology, SA Pathology	RCV000002248	SCV002761826	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2021-07-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476911	SCV002801207	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L; Miyoshi muscular dystrophy 3	2024-02-05	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000082844	SCV002818219	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000002248	SCV003841578	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2023-02-23	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003332991	SCV004041208	pathogenic	ANO5-related muscular dystrophy	2023-08-02	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV000002248	SCV005196403	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2024-08-16	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV000002248	SCV005382149	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2022-11-29	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PS4, PM3, PP5; Variant was found in heterozygous state.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002248	SCV005398731	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2021-05-06	criteria provided, single submitter	clinical testing	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
OMIM	RCV000002247	SCV000022405	pathogenic	Miyoshi muscular dystrophy 3	2012-03-20	no assertion criteria provided	literature only
ANO5 @LOVD	RCV000082844	SCV000172417	not provided	not provided		no assertion provided	not provided
OMIM	RCV000002248	SCV000809056	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2012-03-20	no assertion criteria provided	literature only
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251667	SCV001427407	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000778317	SCV001749728	not provided	ANO5-related disorder		no assertion provided	phenotyping only	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082844	SCV001797445	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000082844	SCV001925201	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082844	SCV001927435	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000082844	SCV001974455	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000002248	SCV002011774	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2021-08-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000778317	SCV004109121	pathogenic	ANO5-related disorder	2023-12-06	no assertion criteria provided	clinical testing	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.