ClinVar Miner

Submissions for variant NM_018075.5(ANO10):c.132dup (p.Asp45fs) (rs540331226)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000311100 SCV000329065 pathogenic not provided 2017-11-30 criteria provided, single submitter clinical testing he c.132dupA pathogenic variant in the ANO10 gene has been reported previously in association with autosomal recessive spinocerebellar ataxia (Balreira et al., 2014; Renaud et al., 2014). The c.132dupA variant causes a frameshift starting with codon Aspartic Acid 45, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asp45ArgfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies demonstrate that the c.132dupA variant results in a significant reduction of ANO10 expression (Balreira et al., 2014). The c.132dupA variant is observed in 15/30,398 (0.049%) alleles in large population cohorts and no individuals were were reported to be homozygous (Lek et al., 2016). We interpret c.132dupA as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000149437 SCV000593208 pathogenic Spinocerebellar ataxia, autosomal recessive 10 2016-11-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000311100 SCV000612337 pathogenic not provided 2016-02-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000311100 SCV000862732 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825557 SCV000966877 pathogenic Autosomal recessive cerebellar ataxia 2018-05-10 criteria provided, single submitter clinical testing The p.Asp45fs variant in ANO10 has been previously reported in 6 compound hetero zygous individuals and 2 homozygous individuals with adult-onset autosomal reces sive spinocerebellar ataxia (Renaud 2014, Balreira 2014, Fogel 2014, Minnerop 20 15). This variant has also been identified in 0.08% (12/14786) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs540331226). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency for autosomal recessive spinocerebellar ataxia. This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 162016). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 45 and leads to a premature termination codo n 9 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. In summary, the p.Asp45fs variant meets criteria to be c lassified as pathogenic for adult-onset autosomal recessive spinocerebellar atax ia. ACMG/AMP Criteria applied: PVS1; PM3_Strong.
OMIM RCV000149437 SCV000196075 pathogenic Spinocerebellar ataxia, autosomal recessive 10 2014-11-01 no assertion criteria provided literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000149437 SCV000965816 likely pathogenic Spinocerebellar ataxia, autosomal recessive 10 no assertion criteria provided clinical testing

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