ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.692G>T (p.Gly231Val) (rs137854523)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082853 SCV000232828 pathogenic not provided 2016-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000082853 SCV000329637 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The G231V pathogenic variant in the ANO5 gene has been previously reported previously in association with LGMD2L and hyperCKemia in the homozygous state and in individuals who harbored an additional pathogenic ANO5 variant (Sarkozy et al., 2012; Bolduc et al., 2010; Wahbi et al., 2013; Savarese et al., 2015). The G231V variant is a conservative amino acid substitution and is observed in 253/276660 (0.09%) alleles in large population cohorts, including one homozygote (Lek et al., 2016). However, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, the majority of missense variants in the ANO5 gene are considered pathogenic (Stenson et al., 2014). We interpret G231V as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000369126 SCV000369971 pathogenic ANO5-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000627782 SCV000645882 likely pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 231 of the ANO5 protein (p.Gly231Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs137854523, ExAC 0.4%). This variant has been reported in the homozygous and compound heterozygous state in several individuals affected with limb-girdle muscular dystrophy type 2 (LGMD2), Miyoshi-like muscle dystrophy, and hyperCKemia (PMID: 23041008, 25891276, 22402862, 23606453, 23670307, 22980763). ClinVar contains an entry for this variant (Variation ID: 2165). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant (c.191dupA) in an individual affected with LGMD2 (PMID:20096397). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this missense change has been reported in the homozygous and compound heterozygous state in multiple individuals affected with ANO5-related disorders. This evidence indicates that this variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000002249 SCV000882598 likely pathogenic Limb-girdle muscular dystrophy, type 2L 2018-10-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762830 SCV000893189 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L; Miyoshi muscular dystrophy 3 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825558 SCV000966878 pathogenic Hereditary fructosuria 2018-08-30 criteria provided, single submitter clinical testing 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, 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.
Mendelics RCV000988504 SCV001138251 pathogenic Gnathodiaphyseal dysplasia 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000002249 SCV000022407 pathogenic Limb-girdle muscular dystrophy, type 2L 2010-02-12 no assertion criteria provided literature only
GeneReviews RCV000002249 SCV000056226 pathologic Limb-girdle muscular dystrophy, type 2L 2012-11-29 no assertion criteria provided curation Converted during submission to Pathogenic.
ANO5 @LOVD RCV000082853 SCV000172430 not provided not provided no assertion provided not provided

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