Submissions for variant NM_018075.5(ANO10):c.1843G>A (p.Asp615Asn)

gnomAD frequency: 0.00035  dbSNP: rs138000380

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001815207	SCV000593206	uncertain significance	not specified	2021-04-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ANO10 gene demonstrated a sequence change, c.1843G>A, in exon 12 that results in an amino acid change, p.Asp615Asn. The p.Asp615Asn change affects a moderately conserved amino acid residue located in a domain of the ANO10 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp615Asn substitution. This particular amino acid change has been described in the literature in the compound heterozygous state with a pathogenic frameshift ANO10 variant in a patient with ataxia (Balreira et al., 2014). This sequence change has been described in the gnomAD database with a frequency of 0.55% in the Ashkenazi Jewish subpopulation (dbSNP rs138000380). Due to the high allele frequency in the gnomAD population database and the lack of functional studies, the p.Asp615Asn variant is interpreted as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000149438	SCV000915332	uncertain significance	Autosomal recessive spinocerebellar ataxia 10	2017-10-18	criteria provided, single submitter	clinical testing	The ANO10 c.1843G>A (p.Asp615Asn) missense variant has been reported in one study in which it is identified in one individual with adult-onset spinocerebellar ataxia in a compound heterozygous state with a frameshift variant (Balreira et al. 2014). The p.Asp615Asn was absent from the healthy brother and is reported at a frequency of 0.00533 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the limited clinical evidence, the p.Asp615Asn variant is considered to be of unknown significance but suspicious for pathogenicity for autosomal recessive spinocerebellar ataxia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001815207	SCV002600560	uncertain significance	not specified	2022-10-18	criteria provided, single submitter	clinical testing	Variant summary: ANO10 c.1843G>A (p.Asp615Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 250800 control chromosomes, predominantly at a frequency of 0.0055 within the Ashkenazi Jewish subpopulation in the gnomAD database. c.1843G>A has been reported in the literature as a compound heterozygous genotype together with a frameshift variant in an individual affected with Autosomal Recessive Spinocerebellar Ataxia (Balreira_2014). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. It found that the variant did not alter lipid scrambling compared to the wild-type protein in the presence or the absence of calcium (Bushell_2019); however, this does not allow convincing conclusions about the variant effect. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000149438	SCV002799679	uncertain significance	Autosomal recessive spinocerebellar ataxia 10	2022-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514864	SCV003282102	likely benign	not provided	2024-03-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002514864	SCV004154315	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	ANO10: PM2:Supporting, PM3:Supporting
Breakthrough Genomics, Breakthrough Genomics	RCV002514864	SCV005189848	uncertain significance	not provided		criteria provided, single submitter	not provided
Athena Diagnostics	RCV001815207	SCV005621804	likely benign	not specified	2024-02-14	criteria provided, single submitter	clinical testing
OMIM	RCV000149438	SCV000196076	uncertain significance	Autosomal recessive spinocerebellar ataxia 10	2014-11-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000149438	SCV001142328	likely pathogenic	Autosomal recessive spinocerebellar ataxia 10	2020-01-06	no assertion criteria provided	curation	NM_018075.3:c.1843G>A in the ANO10 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Considering the adult-onset, the global allele frequency is 0.0003792 and no homozygous was observed in the gnomAD database, we applied PM2. In addition, this missense variant has been reported in one study in which it is identified in one individual with adult-onset spinocerebellar ataxia in a compound heterozygous state with a frameshift variant (PMID25182700). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PP3; PM3; PP4; PM2.