ClinVar Genomic variation as it relates to human health

Variant summary: ANO5 c.155A>G (p.Asn52Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251140 control in the gnomAD v2 database, including 2 homozygotes. Additionally, the variant allele was observed predominantly at a frequency of 0.0048 within the Latino subpopulation at in the gnomAD v3 database (genomes data). The observed variant frequency within Latino control individuals in the gnomAD v3 database is over one fold of the estimated maximal expected allele frequency for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0048 vs 0.0047), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.155A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Sarkozy_2012, Sarkozy__2013, Wahbi_2013, Lee_2014, Savarese_2015, Nallamilli_2018, Ten Dam_2019, Mair_2020). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7), benign (n=1), likely benign (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

This variant is associated with the following publications: (PMID: 22980763, 23041008, 26810512, 31931849, 32419263, 25891276, 26911675, 25326637, 23606453, 30564623, 30919934, 31517061)

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). 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.

ANO5: PM3:Strong, PM2:Supporting, BP4

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.