ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.2272C>T (p.Arg758Cys) (rs137854529)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000128778 SCV000227733 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000032966 SCV000245577 pathogenic 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 (
Invitae RCV000811162 SCV000951415 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 758 of the ANO5 protein (p.Arg758Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs137854529, ExAC 0.4%). This variant has been reported in the homozygous or compound heterozygous state in several families and individuals affected with limb-girdle muscular dystrophy, distal myopathy and Miyoshi myopathy (PMID:22980763, 21739273, 24803842, 21186264, 25135358). This variant is a frequent mutation in the Finnish population (PMID:20096397, 22402862, 27911336). ClinVar contains an entry for this variant (Variation ID: 2166). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002250 SCV000022408 pathogenic Miyoshi muscular dystrophy 3 2012-03-20 no assertion criteria provided literature only
GeneReviews RCV000002250 SCV000056224 pathologic Miyoshi muscular dystrophy 3 2012-11-29 no assertion criteria provided curation Converted during submission to Pathogenic.
ANO5 @LOVD RCV000128778 SCV000172420 not provided not provided no assertion provided not provided
OMIM RCV000032966 SCV000809057 pathogenic Limb-girdle muscular dystrophy, type 2L 2012-03-20 no assertion criteria provided literature only

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