ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.418G>A (p.Gly140Ser) (rs773857091)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170945 SCV000223505 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing p.Gly140Ser (GGC>AGC): c.418 G>A in exon 1 of the HCN4 gene (NM_005477.2). The G140S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G140S variant was not observed in approximately 3,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G140S 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, this substitution occurs at a position that is not well conserved, and in silico analysis predicts this variant likely does not alter to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with familial arrhythmia, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000533549 SCV000648469 uncertain significance Brugada syndrome 8 2017-07-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 140 of the HCN4 protein (p.Gly140Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. While this variant is present in population databases (rs773857091), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 190786). 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 RCV000763984 SCV000894935 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000170945 SCV000987627 uncertain significance not provided criteria provided, single submitter clinical testing

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