ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.2141C>G (p.Thr714Ser) (rs200631556)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000710577 SCV000840819 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000710577 SCV000226991 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing
GeneDx RCV000710577 SCV000520241 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing The T714S variant has been reported previously in an individual with muscular dystrophy, myalgia, and calf hypertrophy who was heterozygous for T714S and another ANO5 pathogenic variant; however, segregation analysis was not provided and functional characterization of the variant was not performed (Penttilä et al., 2012). The T714S variant was subsequently identified in three individuals with limb-girdle muscular dystrophy who were heterozygous for this change and did not have another identifiable ANO5 pathogenic variant; additional clinical information was not provided and functional characterization of the variant was not completed (Savarese et al., 2015). The T714S variant is observed in 14/10152 (0.14%) alleles from individuals of Ashkenazi Jewish background, including one homozygous individual in the ExAC dataset (Lek et al., 2016). The T714S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000534324 SCV000645902 uncertain significance Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 714 of the ANO5 protein (p.Thr714Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs200631556, ExAC 0.1%). This variant has been reported to occur with a pathogenic variant (p.Met543Asnfs*11 ) in ANO5 in an individual affected with myalgia and calf-hypertrophy (PMID: 22402862). This variant has been observed in an individual affected with muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 195004). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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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