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

dbSNP: rs540331226

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000311100	SCV000329065	pathogenic	not provided	2022-05-17	criteria provided, single submitter	clinical testing	Published functional studies suggest that the variant results in a significant reduction of ANO10 expression (Balreira et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25664551, 27045840, 25133958, 25664549, 30515630, 31423897, 31980526, 25182700, 25089919, 29482223, 29915382)
Athena Diagnostics	RCV000311100	SCV000612337	pathogenic	not provided	2023-02-15	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Eurofins Ntd Llc (ga)	RCV000311100	SCV000862732	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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.
CeGaT Center for Human Genetics Tuebingen	RCV000311100	SCV001249875	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ANO10: PM3:Very Strong, PVS1, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000311100	SCV001447379	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000311100	SCV001449599	likely pathogenic	not provided	2015-05-26	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000311100	SCV001468025	pathogenic	not provided	2020-08-12	criteria provided, single submitter	clinical testing
Invitae	RCV000311100	SCV001579504	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp45Argfs*9) in the ANO10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO10 are known to be pathogenic (PMID: 25089919). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of cerebellar ataxia (PMID: 25089919, 25133958, 25182700). This variant is also known as c.123_124insA and c.132_133insT. ClinVar contains an entry for this variant (Variation ID: 162016). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814069	SCV001755531	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000149437	SCV002016415	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2020-06-24	criteria provided, single submitter	clinical testing
3billion	RCV000149437	SCV002573055	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162016 / PMID: 25089919). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000149437	SCV002761460	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2022-01-19	criteria provided, single submitter	clinical testing	The ANO10 c.132dup variant is classified as Pathogenic (PVS1, PS4, PM3) This ANO10 c.132dup variant is located in exon 2/13 and is predicted to cause a shift in the reading frame at codon 45. The variant has been reported in probands with a clinical presentation of OMIM:613728 (PS4). This variant is present at low frequency in population databases (PM2 not met). This variant has been detected in gnomAD 68 times, but consistently reported as pathogenic / likely pathogenic in the literature. This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). This variant has been reported in trans with other pathogenic variants PMID:25089919, 25182700 The variant has been reported in dbSNP (rs540331226) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162016)
Fulgent Genetics, Fulgent Genetics	RCV000149437	SCV002781522	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2022-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000149437	SCV004804468	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: ANO10 c.132dupA (p.Asp45ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.132dupA has been reported in the literature in multiple individuals affected with Spinocerebellar ataxia 10 (Bogdanova-Mihaylova_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30838263). ClinVar contains an entry for this variant (Variation ID: 162016). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000149437	SCV000196075	uncertain significance	Autosomal recessive spinocerebellar ataxia 10	2014-11-01	no assertion criteria provided	literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000149437	SCV000965816	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2021-12-20	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000149437	SCV002064548	pathogenic	Autosomal recessive spinocerebellar ataxia 10	2021-03-24	no assertion criteria provided	clinical testing	The c.132dup variant results in an amino acid frameshift and creates a premature stop codon 9 amino acids downstream of the change, p.Asp45Argfs*9. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ANO10 protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous states in individuals with cerebellar ataxia (PMIDs: 25089919, 29482223, 25133958, 25664549, 31423897, 29915382). Functional studies have demonstrated that this sequence change decreases the expression of ANO10 (PMID: 25182700). It has been described in the gnomAD database with a population frequency of 0.058% in non-Finnish European subpopulation (dbSNP rs540331226). These collective evidences indicate that c.132dup (p.Asp45Argfs*9) is pathogenic.