ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1444G>A (p.Gly482Arg) (rs794727637)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000178241 SCV000230285 likely pathogenic not provided 2016-06-09 criteria provided, single submitter clinical testing
Invitae RCV000647252 SCV000769041 pathogenic Brugada syndrome 8 2020-07-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 482 of the HCN4 protein (p.Gly482Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with sinus node dysfunction and left ventricular non compaction in several families (PMID: 26206080, 25145517, 25145518, 27173043). ClinVar contains an entry for this variant (Variation ID: 197253). Experimental studies have shown that this missense change causes a deleterious effect on protein function (PMID: 25145518). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000178241 SCV001791508 pathogenic not provided 2020-10-02 no assertion criteria provided clinical testing Reported G482R to segregate with bradycardia and left ventricular non-compaction cardiomyopathy (LVNC) in six members of one Dutch family and in three French sisters (Milano et al., 2014; Millat et al., 2015); Published functional studies showed that G482R mutant subunits were non-functional and showed a dominant-negative effect on the channel current (Milano et al., 2014; Schweizer et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32577394, 30471092, 26688388, 28104484, 25145518, 25145517, 26206080, 27173043, 25642760, 25145519)

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