ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.2636T>C (p.Phe879Ser) (rs1459697236)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000785920 SCV000924498 uncertain significance Limb-girdle muscular dystrophy, type 2L 2018-06-15 criteria provided, single submitter research The heterozygous p.Phe879Ser variant was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy. This variant has been identified in <0.01% (1/111500) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The Phenylalanine (Phe) at position 879 is not conserved in mammals and evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain.
Invitae RCV001212196 SCV001383772 uncertain significance Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2019-06-10 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 879 of the ANO5 protein (p.Phe879Ser). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ANO5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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