Submissions for variant NM_213599.3(ANO5):c.2272C>T (p.Arg758Cys)

gnomAD frequency: 0.00049  dbSNP: rs137854529

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000128778	SCV000227733	pathogenic	not provided	2018-07-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000032966	SCV000245577	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2014-07-28	criteria provided, single submitter	clinical testing	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811162	SCV000951415	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2024-01-22	criteria provided, single submitter	clinical testing	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000032966	SCV001164480	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2018-12-03	criteria provided, single submitter	research	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).
CeGaT Center for Human Genetics Tuebingen	RCV000128778	SCV001247615	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ANO5: PM3:Very Strong, PM2:Supporting, PP1, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000128778	SCV001446828	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000128778	SCV001770819	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	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, 37273706, 27911336, 24803842, 17132147, 31395899, 22980763, 21186264, 20096397, 30564623, 30919934, 25135358, 31341644, 28489263, 25891276, 22402862, 31589614, 34008892, 34418069, 35239206)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000002250	SCV001976877	likely pathogenic	Miyoshi muscular dystrophy 3	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PM3, PP3, PP5
Revvity Omics, Revvity	RCV000128778	SCV002017059	pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000032966	SCV002503759	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2023-03-30	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000128778	SCV002520046	pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing	PP1, PP3, PM3_strong, PS4
MGZ Medical Genetics Center	RCV000032966	SCV002581057	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2022-07-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000002250	SCV004045791	pathogenic	Miyoshi muscular dystrophy 3	2022-11-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000128778	SCV004229883	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000002250	SCV000022408	pathogenic	Miyoshi muscular dystrophy 3	2012-03-20	no assertion criteria provided	literature only
GeneReviews	RCV000002250	SCV000056224	not provided	Miyoshi muscular dystrophy 3		no assertion provided	literature only
ANO5 @LOVD	RCV000128778	SCV000172420	not provided	not provided		no assertion provided	not provided
OMIM	RCV000032966	SCV000809057	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2012-03-20	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000002250	SCV001142419	pathogenic	Miyoshi muscular dystrophy 3	2020-01-06	no assertion criteria provided	curation	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000128778	SCV001739975	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000128778	SCV001955179	likely pathogenic	not provided		no assertion criteria provided	clinical testing