ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3582A>G (p.Pro1194=) (rs375637572)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579016 SCV000681261 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The c.3582 A>G variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/32542 (0.025%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). The c.3582 A>G variant results in a synonymous change of the P1194 residue in the HCN4 gene. Although this substitution occurs at a position that is not conserved across species, and guanine (G) is the wild type nucleotide in multiple species, in silico splice prediction algorithms suggest that this variant may create a cryptic splice donor site, upstream of the natural splice donor site, leading to abnormal splicing in the HCN4 gene. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Invitae RCV001041740 SCV001205373 uncertain significance Brugada syndrome 8 2020-10-15 criteria provided, single submitter clinical testing This sequence change affects codon 1194 of the HCN4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HCN4 protein. This variant is present in population databases (rs375637572, ExAC 0.03%). This variant has not been reported in the literature in individuals with HCN4-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, 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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