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
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
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000149437 SCV000965816 likely pathogenic Spinocerebellar ataxia, autosomal recessive 10 no assertion criteria provided clinical testing
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
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

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