Submissions for variant NM_018075.5(ANO10):c.512T>C (p.Phe171Ser)

gnomAD frequency: 0.00004  dbSNP: rs373386030

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516772	SCV000612348	uncertain significance	not specified	2017-03-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778699	SCV000915052	uncertain significance	Autosomal recessive spinocerebellar ataxia 10	2018-09-17	criteria provided, single submitter	clinical testing	The ANO10 c.512T>C (p.Phe171Ser) missense variant has been reported in a compound heterozygous state with a second frameshift variant in one individual affected with autosomal recessive cerebellar ataxia (Renaud M et al. 2014). Control data are unavailable for this variant. The p.Phe171Ser variant is reported at a frequency of 0.000063 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Phe171Ser variant is classified a variant 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	RCV000516772	SCV004037720	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: ANO10 c.512T>C (p.Phe171Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251062 control chromosomes (gnomAD). c.512T>C has been reported in the literature in individuals affected with cerebellar ataxia (Renaud_2014, Benkirane_2021), and one was reported as compound heterozygous with a (likely) pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25089919, 34234304). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV003558436	SCV004292685	likely pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 171 of the ANO10 protein (p.Phe171Ser). This variant is present in population databases (rs373386030, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of spinocerebellar ataxia (PMID: 25089919, 34234304). ClinVar contains an entry for this variant (Variation ID: 446836). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO10 protein function. Experimental studies have shown that this missense change affects ANO10 function (PMID: 32620747). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.