ClinVar Miner

Submissions for variant NM_014391.3(ANKRD1):c.838A>G (p.Ile280Val) (rs144770680)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150156 SCV000197042 likely benign not specified 2013-11-05 criteria provided, single submitter clinical testing Ile280Val in exon 8 of ANKRD1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the variant amino acid, valine (Val), has been identified in 7 other mammals (lemur, rat, mouse, horse, cow, alpaca, and opossum) despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2, SI FT) do not suggest a high likelihood of impact to the protein. Finally, it has b een identified in 3/8600 European American chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s144770680). Ile280Val in exon 8 of ANKRD1 (rs144770680; allele frequency = 3/8 600) **
GeneDx RCV000766742 SCV000520826 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing The I280V variant of uncertain significance in the ANKRD1 gene has been reported previously in association with HCM (Arimura et al., 2009). The I280V variant is observed in 9/126396 (0.007%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The I280V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, expression of I280V in COS-7 cells revealed this variant increased binding to titin/connectin and myopalladin and altered protein localization in cardiomyocytes (Arimura et al., 2009). Additional studies demonstrated that I280V expression in engineered heart tissues resulted in an unstable protein that did not incorporate into the sarcomere, however, inhibition of the proteasome led to protein stability, incorporation into the sarcomere, and prolonged relaxation (Crocini et al., 2013).
Invitae RCV000823178 SCV000964027 uncertain significance ANKRD1-related dilated cardiomyopathy 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 280 of the ANKRD1 protein (p.Ile280Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs144770680, ExAC 0.006%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 19608031). ClinVar contains an entry for this variant (Variation ID: 162746). Experimental studies have shown that this missense change increases the binding of ANKRD1 protein to both titin/connectin and myopalladin, leading to the ANRD1 protein mislocalization (PMID: 19608031, 23572067). 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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