ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2917G>A (p.Gly973Arg) (rs200495478)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691006 SCV000818744 uncertain significance Brugada syndrome 8 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 973 of the HCN4 protein (p.Gly973Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200495478, ExAC 0.02%). This variant has been observed in individual(s) with sudden unexpected death in epilepsy (PMID: 21615589). ClinVar contains an entry for this variant (Variation ID: 570199). 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 and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000763982 SCV000894933 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000995391 SCV001149526 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001118934 SCV001277255 uncertain significance Sick sinus syndrome 2, autosomal dominant 2017-06-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV000995391 SCV001770793 uncertain significance not provided 2021-03-23 criteria provided, single submitter clinical testing Reported previously in one individual with sudden unexplained death (SUD) and a history of epilepsy (Tu et al., 2011; Goldman et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21615589, 31018519, 33013630, 30452770, 26749013)

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