ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2527G>A (p.Ala843Thr) (rs777023781)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000733914 SCV000223502 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing p.Ala843Thr (GCC>ACC): c.2527 G>A in exon 8 of the HCN4 gene (NM_005477.2). The A843T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Data from control individuals were not available to assess whether A843T may be a common benign variant in the general population. The A843T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals when present. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Only one missense mutation in a nearby residue (S841L) has been reported in association with Brugada syndrome. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000733914 SCV000862019 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing
Invitae RCV001062392 SCV001227189 uncertain significance Brugada syndrome 8 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 843 of the HCN4 protein (p.Ala843Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs777023781, ExAC 0.009%). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 190783). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Not Available; Align-GVGD: Class C5. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. 5

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