ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1441T>C (p.Tyr481His) (rs1057519275)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693647 SCV000821523 uncertain significance Brugada syndrome 8 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 481 of the HCN4 protein (p.Tyr481His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with left ventricular non-compaction in 2 families and to be present in a third unrelated case (PMID: 25145517, 27173043). ClinVar contains an entry for this variant (Variation ID: 374860). Experimental studies have shown that this missense change reduces HCN4 channel current density  (PMID: 25145517). 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000415538 SCV001428869 pathogenic Sick sinus syndrome 2, autosomal dominant 2018-07-25 criteria provided, single submitter clinical testing
OMIM RCV000415538 SCV000493946 pathogenic Sick sinus syndrome 2, autosomal dominant 2014-08-26 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529223 SCV001742311 pathogenic not provided no assertion criteria provided clinical testing

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