ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2701G>A (p.Ala901Thr) (rs201742383)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464894 SCV000541553 uncertain significance Brugada syndrome 8 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 901 of the HCN4 protein (p.Ala901Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs201742383, ExAC 0.02%) but has not been reported in the literature in individuals with a HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 404120). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480340 SCV000574427 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. Although the A901T variant has not been published to our knowledge, it has been observed both independently, and in conjunction with additional cardiogenetic variants, in other individuals referred for cardiac genetic testing at GeneDx, although no segregation data are available to further clarify the role of this variant in disease. This variant is also observed 20/97234 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The A901T 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Ambry Genetics RCV000619580 SCV000737765 likely benign Cardiovascular phenotype 2016-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)

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